Mast Cell Mediators: Their Differential Release and the Secretory Pathways Involved

Abstract

Mast cells (MC) are widely distributed throughout the body and are common at mucosal surfaces, a major host–environment interface. MC are functionally and phenotypically heterogeneous depending on the microenvironment in which they mature. Although MC have been classically viewed as effector cells of IgE-mediated allergic diseases, they are also recognized as important in host defense, innate and acquired immunity, homeostatic responses, and immunoregulation. MC activation can induce release of pre-formed mediators such as histamine from their granules, as well as release of de novo synthesized lipid mediators, cytokines, and chemokines that play diverse roles, not only in allergic reactions but also in numerous physiological and pathophysiological responses. Indeed, MC release their mediators in a discriminating and chronological manner, depending upon the stimuli involved and their signaling cascades (e.g., IgE-mediated or Toll-like receptor-mediated). However, the precise mechanisms underlying differential mediator release in response to these stimuli are poorly known. This review summarizes our knowledge of MC mediators and will focus on what is known about the discriminatory release of these mediators dependent upon diverse stimuli, MC phenotypes, and species of origin, as well as on the intracellular synthesis, storage, and secretory processes involved.

Introduction

Human mast cells (MC) are often characterized by their ability to release a variety of important mediators with a diversity of biological activities (1). The regulated release of peptides, amines, lipids, and even some gases depends on several molecular pathways: a prominent one of which releases large dense core vesicles (granules) through regulated exocytosis (degranulation); other pathways depend upon de novo production of mediators and complex vesicle trafficking and recycling, including constitutive secretion, exosomal and endosomal pathways; and other secretory pathways that are not dependent upon vesicles or membrane-bound moieties [e.g., gases such as nitric oxide by diffusion (2), lipid mediators from lipid bodies]. Although research is providing important new insights, we understand remarkably little about how the mediators are sorted into these secretory pathways and differentially released (Tables 1 and 2). Unanswered questions include: how are these pathways similar/dissimilar; how are mediators sorted into various compartments (e.g., progranules, granules, lysosomes, secretory vesicles, and exosomes); which stimuli activate these secretory pathways, and which proteins are involved; how do MC selectively release different cargo given different stimuli?

Constitutive exocytosis occurs in the absence of discernable stimuli for trafficking of secretory vesicles to the plasma membrane and can occur throughout the lifetime of a cell (3). Regulated exocytosis occurs after a clearly defined stimulus, either through changes in the extracellular environment [temperature (4, 5), pH (6), radiation (7), or osmolarity (8)] or ligation of a cell surface receptor (9). The pathways that control constitutive and regulated exocytosis have been extensively studied using powerful tools in high-resolution microscopy, molecular biology and animal model systems, and some of the molecules involved have been identified.

The terms degranulation, secretion, and exocytosis are often used interchangeably but have subtle variations in meaning. Degranulation refers to the loss of or release of granules and is most often associated with MC and basophils, both of which are characterized by their large intracellular granules. Secretion involves the release of a substance from one place of containment to another, i.e., from a cell to its extracellular environment or a gland to the skin’s surface. Excretion is the elimination of a waste material from a cell or organ. Exocytosis is a process of cellular secretion or excretion in which substances contained in vesicles are discharged from the cell by fusion of the vesicular membrane with the outer cell membrane (10–12). MC exhibit all forms of these release events but MC are perhaps best known for their rapid secretion of granules (degranulation) that contain large stores of pre-formed mediators (9).

This review identifies our current understanding of the biogenesis of various mediator compartments, and the mechanisms of sorting and release of mediators from these compartments (Figure 1). We present some new postulates about exocytosis that may be particularly relevant to the MC, a highly specialized secretory cell (13). We also refer the readers some excellent recent articles for more details on various aspects of this subject (9, 14–19).

Figure 1

Pre-Stored Mediator Release from MC Granules

Mediators stored in MC granules

Mast cells are morphologically characterized by numerous, electron dense cytoplasmic granules which contain biogenic amines [histamine, serotonin] (20); several serine and other proteases {e.g., tryptase-α, -βI, -βII, -βIII, -γ [protease, serine S1 family member (PRSS) 31], -δ, chymase-1, cathepsin G, granzyme B, and carboxypeptidase A3} (21–31); lysosomal enzymes [β-glucuronidase (20), β-hexosaminidase (20), arylsulfatase (20)]; some cytokines [TNF (32), bFGF (33), IL-4 (34), and SCF (35)]; and proteoglycans [heparin (36, 37), chondroitin sulfates (36)] (Table 1). MC are able to overcome the large thermodynamic hurdle of storing high concentrations of these mediators in their granules by trapping them in an anionic gel matrix composed of chondroitin sulfates and heparin (38).

Subtypes of human MC are distinguished by the presence or absence of different serine proteases in their granules (i.e., tryptase⁺/chymase⁻: MC_T, tryptase⁺/chymase⁺: MC_TC, and tryptase⁻/chymase⁺: MC_C). MC activation has typically been measured by monitoring the release of granule mediators (degranulation), with a particular focus on histamine, β-hexosaminidase, or tryptase (39, 40). Pre-stored mediator release through MC degranulation can be an early and rapid event following stimulation, resulting in the release of large portions of stored histamine within 15–90 s. This release of pre-formed mediators enables not only rapid anaphylactic reactions and allergic responses but also initiates recruitment of leukocytes to sites of pathogen invasion, activation of innate immune processes, and inflammatory responses (1). Other longer term responses associated with granule-derived mediators include wound healing and tissue remodeling processes through multiple communications with other cells (e.g., fibroblast proliferation and extracellular matrix production by histamine and MC proteases) (41).

MC granule heterogeneity and biogenesis

Heterogeneity

Mast cells granules, also called secretory lysosomes, contain both lysosomal proteins such as acid hydrolases, e.g., β-hexosaminidase, as well as mediators such as histamine, and can secrete both together. MC also contain traditional lysosomes that can release enzymes such as β-hexosaminidase independently of histamine (42). Raposo et al. (43) distinguished three types of granules in mouse bone marrow-derived MC (BMMC) based on their contents of MHC class II, the lysosomal marker β-hexosaminidase, lysosomal membrane protein (LAMP)-1, LAMP-2 and mannose-6-phosphate receptors (M6PR), and the biogenic amine, serotonin: type I granules contain MHC class II, β-hexosaminidase, LAMP-1, LAMP-2, and M6PR but not serotonin (perhaps a classical lysosome); type II granules contain MHC class II, β-hexosaminidase, LAMP-1, LAMP-2, M6PR, and serotonin (perhaps a late secretory lysosome); type III granules contain β-hexosaminidase and serotonin but not MHC class II (Table 3) (42, 43). Baram et al. proposed a model wherein type II granules are generated by fusion of type I and type III granules, which contain lysosomal proteins and secretory amines, respectively (42). However, there has been little experimental follow-up of this postulate and there is evidence that MC have more diverse types of granules than depicted by this model (Figure 2). Indeed, the relationship between this classification of granules and observations that serotonin and cathepsin D vs. histamine and TNF exist in distinct granule populations (see below) in mouse MC is unclear (44). It is likely that MC granules are more heterogeneous than the three types shown above (Figure 2; Table 3) and that this heterogeneity may depend on the tissue of residence and the species, health status, and even age of the individual (1, 45).

Figure 2

Biogenesis

The biogenesis of MC granules involves regulated fusion of what are called unit granules (small fusogenic granules) (46). These early unit granules buds from the trans-Golgi region and fuse to generate progranules in a region delimited by the outermost Golgi cisternae, rough endoplasmic reticulum (ER), and mature granules in the cytoplasm. The volumes of progranules are multiples of unit granules (i.e., volume of progranule created by three unit granules is three times unit granule volume). Progranules leave this zone as immature granules and become mature through a fusion process with other immature or mature granules. A process called “condensation” reduces the granule volume and organizes the contents, generating various sizes of mature granules (15). In addition to the homotypic fusion, which is postulated to form type III granules, immature granules or type III granules are also able to fuse to endosomes or lysosomes (Type I granules) in what might be the pathway that forms type II granules (secretory lysosomes) as Baram et al. proposed (see above and Figure 2) (42, 43). However, MC granules are likely more heterogeneous than the three types postulated, and our understanding of the later phase of granule biogenesis is thus depicted inside a black area in Figure 2.

Molecules involved in MC granule biogenesis

Several proteins involved in MC granule biogenesis and maturation have been identified (Table 4).

Rab GTPases

Rab3d and Rab5 play roles in the fusion of immature granules. MC from Rab3d knockout mice have granules that are larger than in MC from wild-type mice (47), while knockdown of endogenous Rab5 or expression of constitutively negative mutants of Rab5 significantly reduces the size of granules and increases their number (48). Moreover, Rab5 plays a role not only in homotypic granule fusion (type III granule biogenesis) but also in granule/endosome heterotypic fusion (type II granule biogenesis), and vesicle associated membrane protein (VAMP)-8 is involved in Rab5-mediated fusion of granules.

Lysosomal trafficking regulator

Chediak–Higashi syndrome, a mutation of the lysosomal trafficking regulator (LYST) causes the formation of giant granules in many cells including MC, and can be studied using the orthologous lyst-deficient beige (Lyst^bg/Lyst^bg) mouse. In MC and pancreatic acinar cells of beige mice, there is giant granule formation, presumably the result of disordered fusion of granules, suggesting Chediak–Higashi syndrome (CHS)/Lyst plays a role in controlling granule fusion (15, 49).

Synaptotagmins

The synaptotagmins (Syts) are membrane-trafficking proteins with at least 15 members in mammals. The RBL-2H3 MC line expresses Syt II, III, V, and IX (42) and RBL-2H3 treated with antisense to Syt III showed enlarged granule size, impairment in granule maturation, and formation and delivery of internalized transferrin to the perinuclear endocytic recycling compartment involved in a slow recycling pathway (50).

Granin family

The granin family of proteins, first described in neuroendocrine cells, are also important in MC granule biogenesis and maturation. Secretogranin III, for example, is present in MC granules, depleted during MC degranulation and over-expression of this protein causes an expansion of the secretory vesicle compartment (51). Although the biologic role of this family of proteins is not well understood, they are involved in cholesterol sequestration, interact with chaperones of granule proteins, serve as precursors of granule cargo and function as calcium buffering proteins, making them potentially intriguing players in the life history of MC granules. Is it possible that some of their many functions are necessary to control progranule fusion and thereby aid their maturation of secretory lysosomes/granules? Could these proteins somehow regulate the core components of the fusion machinery and thereby determine which progranules fuse together? Further experimentation is required in this area.

Histamine and proteoglycans

Some granule mediators themselves such as histamine and the core proteoglycans such as serglycin are also important components of the granule maturation process. For example, BMMC from serglycin knockout mice have functional secretory granules but they are defective in dense core formation (52). Furthermore, these serglycin^−/− BMMC are resistant to apoptosis associated with reduced release of proteases and defective caspase-3 activation (53). In addition, the lack of histamine or the enzymes that control its synthesis significantly alters the morphology and contents of granules. Peritoneal MC from histidine carboxylase knockout mice show abnormal granule morphology and contain fewer proteases and heparin (54). This is mainly due to the down-regulation of genes encoding granule proteases and enzymes involved in heparin biosynthesis. Interestingly, agonists of the H4 histamine receptor and exogenous application of histamine restored granule maturation. Therefore, histamine likely influences early steps in granule maturation but has little role in maintaining the integrity of fully formed mature granules since depletion of histamine from mature MC had no obvious effect on granule structure. It would be interesting to examine the effect of histamine depletion on immature MC (i.e., from CD34⁺ progenitors) as they progress through the MC differentiation process.

Adaptor-protein family

Components of our models of MC granule biogenesis can be extrapolated from other cells with complex secretory granule processes, such as pituitary lactotropes, pancreatic β-cells, and transfected tumor cells. In these cells, progranules in the trans cisterna of the Golgi are covered with clathrin coats, which contain the adaptor-protein (AP) family of proteins that can bind cytosolic tails of transmembrane protein cargo, facilitating their entry into budding vesicles (55). Immature secretory granules are not responsive to secretagogues and it appears that one of the essential roles of the AP proteins is to facilitate their maturation (56). Could APs perform a similar function in MC? Clearly, additional studies are needed to further understand the genesis, heterogeneity, and plasticity of MC granules and uncover potential therapeutic opportunities within such knowledge; a frontier.

Mechanisms of sorting and storage of pre-formed mediators in MC granules

The most unique and igneous feature of MC granules is their ability to store large concentrations of mediators in a small space for long periods. In theory, collecting a high concentration of such highly charged mediators in a membrane-enclosed space would require a large amount of osmotic work and create a thermodynamic disadvantage. However, MC trap the mediators in an anionic gel matrix composed mainly of heparin and chondroitin sulfate, which confers a huge thermodynamic advantage (38, 57). Upon cell activation, the polymer gel phase undergoes a transition and swells to release the mediators (58). This efficient solution is not-surprisingly conserved among living organisms and even phytoplankton use a similar packaging and degranulation process (59). Current understanding of sorting and storage mechanisms of pre-formed mediators are reviewed below and in Table 1 but it is still poorly understood.

Proteoglycans

Proteoglycans, a core component of MC granules are heavily glycosylated proteins, consisting of a core protein and glycosaminoglycan side chains that are covalently attached to the core through glycosidic bonds. In MC, serglycin is a dominant core protein, and heparin and chondroitin sulfate are dominant glycosaminoglycans that can be used to distinguish some MC subpopulations (1). Sulfation of glycosaminoglycans imparts a negative charge on the proteoglycan, which is an important mechanism that helps to retain proteases and biogenic amines in MC granules (60). An ion exchange mechanism with the charged glycosaminoglycans is thought to be significant in mediator release from granules (61, 62). Moreover, as outlined above, proteoglycans are important in granule composition and maturation. However, details of the sorting mechanism of proteoglycans and other mediators into MC granules are poorly understood. Studies with rat pancreatic acinar cells provide clues and suggest that glycosaminoglycan side chains are necessary for proteoglycan sorting into granules, as deletion of serine–glycine repeat region of the serglycin core protein and treatment with p-nitrophenyl-β-D-xylopyranoside, an alternate substrate for glycosaminoglycan side chain attachment, prevented sorting into granules and lead to accumulation of proteoglycans in Golgi (63).

MC proteases

Mast cell proteases are synthesized in the ER, modified in the Golgi complex, and sorted into progranules that bud from the trans-Golgi. Retention of MC proteases in granules depends on the serglycin proteoglycan in murine MC, as absence of mouse MC protease (mMCP)-5 (chymase) and carboxypeptidase, and reduction of mMCP-6 (tryptase) occurs in the granules of MC from serglycin deficient mice despite normal expression of protease mRNA and granule formation (52). Although limited information is available with other kinds of proteases, serglycin proteoglycan is involved in certain protease retention in MC granules. However, the mechanisms underlying the trafficking of MC proteases into the granule need to be elucidated and confirmed in human MC, although the storage of heparin and chondroitin sulfate proteoglycan in human MC granules has been shown (36).

Biogenic amines

Histamine and serotonin are biogenic amines stored in MC granules. There is evidence that transport of biogenic amines from cytosol into the MC granules occurs in a vesicular monoamine transporter 2 (VMAT2)-dependent manner (64, 65). Moreover, retention of biogenic amines and release from the granule is serglycin proteoglycan dependent (66). Whether retention of both MC proteases and biogenic amines are directly dependent on serglycin proteoglycan or involve only the glycosaminoglycan side chains, e.g., heparin, with their electrostatic charges (67–70), needs to be elucidated and extended to studies with human MC. Some polyamines (such as putrescine, spermidine, and spermine) are required for granule homeostasis and possibly aid in the native conformation and packaging of other granule molecules such as histamines and proteases (71).

Lysosomal enzymes

Many lysosomal enzymes (Table 1) are found in MC granules but the detail mechanisms of their sorting, trafficking, storage, and secretion are poorly understood. It is postulated that they are transported into type II MC granules when granules and endosomes fuse (Figure 2). Clearly, lysosomal enzymes can be found in both type II granules, as well as classical lysosomes (type I granules), and secreted from both compartments. Using MC from serglycin knockout mice, it was shown that storage and release of β-hexosaminidase is independent of serglycin (52).

Cytokines

Among the large number of cytokines and chemokines released after MC activation, TNF (32, 72), bFGF (33), IL-4 (34), and SCF (35) are known to be pre-stored in MC granules, and can be released by regulated exocytosis, as well as synthesized following MC activation and released through constitutive exocytosis (Figure 1) (73, 74). Many other cytokines and chemokines appear not to be stored [e.g., GM-CSF (75)], but are newly synthesized following MC activation and are secreted by constitutive exocytosis over the course of several hours/days (discussed below) (9, 76). For storage in the granule, there appears to be a different trafficking mechanism for TNF in rodent and human MC. In rodent MC, sorting of TNF from ER to granules occurs via a brefeldin A- and monensin-sensitive route, utilizing a M6PR-dependent pathway and N-linked glycosylation of asparagine at N86 (Figure 2) (72). By contrast in human MC, TNF does not utilize this pathway as the N-linked glycosylation motif NSS of rodent TNF is replaced by the RTP motif (32). By transfecting and chasing fluorescence-tagged TNF into human MC lines (HMC-1 and LAD2), Olszewski et al. showed that in human MC, TNF traffics to the plasma membrane transiently, but then is stored in MC granules by endocytosis (Figure 2) (32). These observations emphasize that evidence acquired from studies of rodent MC must be validated for human MC, as has been shown for several other examples of species differences among MC (1). Apart from TNF, the mechanisms of trafficking of bFGF, IL-4, and SCF, another cytokines stored in human MC granules have not been studied, and we still do not fully understand how these cytokines are sorted in granules and which secretion pathway(s) initiates their release. Based on the binding affinity of bFGF for heparin (77), the retention mechanism of bFGF in the granule is likely to be heparin dependent, although this needs to be confirmed. Immunohistochemistry has shown that IL-4 but not IL-5 are stored in MC secretory granules in the lung parenchyma and nasal mucosa of patients with active allergic rhinitis (34). Although the amount of IL-4 in the granules increases after FcεRI-mediated activation, it is unclear whether the majority of IL-4 released extracellularly is due to degranulation or constitutive exocytosis.

Mechanisms of secretion of pre-formed mediators from MC granules

Two types of degranulation have been described for MC: piecemeal degranulation (PMD) and anaphylactic degranulation (AND) (Figures 1 and 2). Both PMD and AND occur in vivo, ex vivo, and in vitro in MC in human (78–82), mouse (83), and rat (84). PMD is selective release of portions of the granule contents, without granule-to-granule and/or granule-to-plasma membrane fusions. PMD in MC has been identified in numerous settings, ranging from chronic psychosocial stress (85) to estradiol (86), CCL2 (87) and TLR stimulation (88), and interactions with CD4⁺/CD25⁺ regulatory T cells (89). The granule morphology is relatively well retained following PMD, although ultrastructural changes are evident (79). It has been proposed that the mechanism of PMD involves the budding of vesicles containing selected mediators from granules and their transport to the plasma membrane, fusion, and mediator release (Figures 1 and 2) (90). Little is known about the molecular machinery involved in these processes.

In contrast to PMD, AND is the explosive release of granule contents or entire granules to the outside of cells after granule-to-granule and/or granule-to-plasma membrane fusions (Figures 1 and 2). Ultrastructural studies show that AND starts with granule swelling and matrix alteration after appropriate stimulation (e.g., FcεRI-crosslinking). Granule-to-granule membrane fusions, degranulation channel formation, and pore formation occur, followed by granule matrix extrusion (81). Granule-to-granule and/or granule-to-plasma membrane fusions in AND are mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) (91). In human intestinal MC, protein expression of soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP)-23, syntaxin (STX)-1B, STX-2, STX-3, STX-4, VAMP-2, VAMP-3, VAMP-7, VAMP-8, and STX-6 have been reported (92). However, only VAMP-7 and VAMP-8 were found to translocate to the plasma membrane and interact with SNAP-23 or STX-4 upon activation. Moreover, inhibition of SNAP-23, STX-4, VAMP-7, or VAMP-8, but not VAMP-2 or VAMP-3, reduced histamine release mediated by FcεRI-crosslinking (92). Therefore, VAMP-7, VAMP-8, SNAP-23, and STX-4 are important SNARE molecules in human intestinal MC granule fusion and exocytosis.

Molecules involved in MC degranulation

Several proteins involved in MC degranulation were listed in Table 5.

Mammalian uncoordinated-18 proteins

The functions of SNARE proteins are regulated by several accessory proteins, but our knowledge is incomplete and at least in part, the information is controversial (Table 5). Munc 13-4 was shown to be a target of Rab27a and Munc 13-4-transduced RBL-2H3 release more histamine compare to the mock-transduced cells after IgE/Ag stimulation (93). In rodent MC, mammalian uncoordinated-18 (Munc-18)-2, located in the granule membrane, interacts with STX-3 and plays a role in granule-to-granule as well as granule-to-plasma membrane fusion (94, 95) whereas, Munc-18-3, located in the plasma membrane, also interacts with STX-4 (94). Following activation of RBL-2H3, another protein, complexin II translocates from the cytosol to the plasma membrane and interacts with a SNARE complex. Although translocation of complexin II to the plasma membrane did not induce membrane fusion, the reduction of degranulation after knockdown of this protein suggests that complexin II is a positive regulator of MC degranulation (96). The fusion of the SNAREs with the plasma membrane has been examined using transmission and freeze-fracture electron microscopy and biophysical modeling. About 30–60 s after activation, unetchable circular impressions about 80–100 nm in diameter were found on the E face (intracellular face) of the plasma membrane (97). These impressions are not permanent but are postulated to form the fusion sites for the granules directly preceding degranulation. Under certain conditions, these fusion sites can form rosettes and the coupling of this structure with the plasma membrane may then form a cup-shaped structure called a porosome (98). Due to the nanometer size of these SNARE docking sites, the MC degranulation complex has been called a nano-machine (97).

Vesicle associated membrane proteins

A study using BMMC from VAMP-8 deficient mice showed reduced serotonin, cathepsin D, and β-hexosaminidase release, but normal histamine and TNF release following IgE-mediated or PMA/ionomycin stimulation (44). By contrast, transfection of VAMP-8 in RBL-2H-3 did not affect the calcium ionophore/12-O-tetradecanoyl-13-acetate- or IgE-mediated release of fluorescent-labeled neuropeptide Y, which is stored in the same granules as serotonin and β-hexosaminidase (48). These conflicting data may be the result of different experimental systems (former using deficient mouse of VAMP-8 and latter using over-expression), or the fact that the latter study examined mediator release indirectly with fluorescent-labeled neuropeptide Y. Although further study is required, VAMP-8 is likely involved in granule biogenesis and degranulation of subsets of MC granules, which contain serotonin, cathepsin D, and β-hexosaminidase. Moreover, this suggests that there is heterogeneity of MC granules (Figure 2), and that distinct mechanisms are involved in mediator release between subsets of granules.

Synaptotagmins

Synaptotagmin (Syt) II depresses Ca²⁺-triggered secretion of β-hexosaminidase and MHC class II release (42), but increases cathepsin D release in RBL-2H3 and mouse BMMC (99). Moreover, in Syt II knockout mice there is a marked deficiency in degranulation and an impaired passive cutaneous anaphylaxis response (62). In RBL-2H3, Syt IX can regulate protein export from the endocytic recycling compartment to the plasma membrane and play a role in sorting proteins of secretory granules (100). Much remains to be learned about these proteins and MC function.

Rab GTPases

In addition to their role in granulogenesis mentioned above, the Rab family of GTPases is also involved in MC degranulation. Over-expression of Rab3a in RBL-2H3 showed no (101), or inhibitory effects (102) on FcεRI-mediated β-hexosaminidase release, while over-expression of Rab3d demonstrated that it translocates from the granule to the plasma membrane (103), and inhibits degranulation (101). Recently, it was established that Rab27a is located in histamine-containing granules in RBL-2H3 and that over-expression of constitutively active Rab27a reduced FcεRI-mediated histamine secretion (93). Munc 13-4 was found to be a target of Rab27a, and the Rab27a-Munc 13-4 complex was required for docking of granules to the plasma membrane and release of granule contents in RBL-2H3 cells (104). Moreover, Rab27a regulates cortical actin stability with its effectors melanophilin (Mlph) and myosin, as well as Rab27a/b/Munc13-4-dependent granule exocytosis (105). Rab27b knockout mice exhibited reduced passive cutaneous anaphylaxis and defects in FcεRI-mediated β-hexosaminidase release from BMMC (106). Although Rab5 is involved in MC granule biogenesis (see above), a transfection study showed that Rab5 is not involved in granule mediator release (48).

Rho GTPases

Among Rho GTPases, Rac and Cdc42 play a positive role in RBL-2H3 degranulation by regulating IP₃ production, upstream of Ca²⁺ influx and interacting with PLCγ1 (107, 108). More recently, the roles of Rac1 and Rac2, which have a 92% sequence identity, in MC degranulation were dissected using knockout mice (109). In BMMC from Rac2 knockout mice, FcεRI-, but not Ca²⁺ ionophore-mediated β-hexosaminidase release was defective because of a decrease in Ca²⁺ flux without changing F-actin remodeling and membrane ruffling, which are regulated by Rac1 (109).

Others

The cytoskeleton and the microtubule network is an essential component of the degranulation process in MC. Proteins such as DOCK5 (110), MARCKS (111), and myosin VI (112) regulate the progress of secretory granules through the cytoskeletal network and allow them to dock with the plasma membrane. When these proteins are disrupted, the degranulation process does not occur normally. Some of these pathways remain unexplored in MC, yet we know that some microtubule events facilitate granule fusion and are essential to degranulation. For example, myosin Va forms a complex with Rab27a and Mlph thereby regulating cortical F-actin stability upstream of Rab27a/b/Munc13-4-dependent granule exocytosis (105).

Although calcium flux is unequivocally an essential feature of the degranulation process [recently reviewed by Fahrner et al. (113) and Ashmole and Bradding (114)], other ion exchange complexes have also been implicated, such as potassium and chloride channels that facilitate and regulate Ca²⁺ signaling. Certainly, disruption of membrane potentials using cationic liposomes can impair Ca²⁺ flux and suppress the function of SNAP-23 and STX-4 (115). It has been suggested that inhibitors of these ion exchange pathways may be useful in the treatment of inflammatory diseases that are mediated by MC activation and degranulation (116).

Calcium flux is essential for degranulation but its role may be more extensive than first postulated and some theories have questioned the long-standing belief that granule membranes must fuse with the plasma membrane to facilitate exocytosis. There are new theories of exocytosis that have not yet been examined in MC, including the theory of porocytosis, or secretion without membrane fusion, in which Ca²⁺ ions form salt bridges among adjacent lipid molecules through which mediators would move according to mass action (13). This quantal secretion theory has been postulated to be important in neuromuscular junctions and the central nervous system and it offers an intriguing process for mechanisms underlying constitutive exocytosis. However, this mathematical model has not been validated experimentally in neurons or other secretory cells. Autophagy, an evolutionarily conserved bulk degradation system that facilitates the clearance of intracellular molecules, has also been shown to be an important regulator of MC exocytosis. A recent study by Ushio et al. has shown that proteins that normally control autophagy may also facilitate the fusion of small secretory vesicles and facilitate their fusion with the plasma membrane (117). In fact, many new regulatory pathways have been connected to degranulation and exocytosis. However, we need more sophisticated model system to validate these new theories. Given that most molecules known to be involved in MC degranulation have been studied in rodent models, their roles in human MC must be examined and potential distinctions between MC phenotypes in different species should be investigated.

Secretion of Exosomes

Exosomes are membrane-bound vesicles of ~30–100 nm that appear to bud from the internal surface of multivesicular bodies in the endosomal compartment of many cell types including MC (Figure 1) (118). They are important in cell–cell communications and a breadth of physiological and pathophysiological responses, notably antigen presentation and host defenses. The contents of exosomes include a richness of lipids such as ceramide, cholesterol, phosphatidylserine, and sphingomyelin; a great diversity of proteins (200–400) including MHC class II, phospholipases, heat shock proteins, co-stimulatory molecules (CD40, CD40L, and CD86), adhesion molecules, kinases, tetraspanins, cytoskeletal proteins, chaperones, aldolase A, TNF, FcεRI chains, processed peptides from antigens; and a plethora of mRNA (>1800) and microRNA (>100) species (119–122). Exosomes transfer diverse cargo and functional capacity among cells; for example, mRNAs and microRNAs in MC exosomes can be transferred between human and mouse MC or other cells and control gene expression in recipient cells (119, 120). Carroll-Portillo et al. emphasized the potential functional significance of IgE-antigen and antigenic peptide–MHC class II MC–T cell–Dendritic cell interactions, as well as MC uptake of antigen-crosslinked receptor (16).

Mast cell exosomes can be secreted by both constitutive or regulated exocytosis (Figure 1) (16, 43) and the composition of protein constituents differs depending upon which pathway is employed (16). Knowledge is advancing rapidly about the molecular bases of exosome biogenesis, regulation of exosome loading, and the secretory pathways involved. The reader is referred to recent reviews of this intriguing and rapidly evolving subject (118, 123).

Cytokine/Chemokine Secretion from Compartments Other than Secretory Lysosomes

In addition to regulated secretion of a limited repertoire of cytokines from stores in granules (above) through pathways of PMD or AND, MC secrete a diversity of cytokines and chemokines by other pathways [diagrammed by Lorentz et al. (14) in their Figure 3], including: constitutive exocytosis, better known in macrophages [e.g., Ref. (3, 9), etc.], and exosomal secretion (Figure 1). Frank et al. showed that involvement of SNAREs in chemokine release of human intestinal MC using their specific neutralizing antibodies. They showed that CXCL8, CCL2, CCL3, and CCL4 release after IgE/α-IgE stimulation were abrogated by inhibition of STX-3 or SNAP-23, but not by inhibition of STX-2 or VAMP-3. Moreover, inhibition of different SNARE subsets selectively reduce chemokine release (i.e., STX-4 or VAMP-8 inhibition selectively reduce CXCL8, and STX-6 inhibition reduces CXCL8 and CCL2) (124). However, other study using VAMP-8^−/− BMMC showed that VAMP-8 does not affect cytokine/chemokine secretion (125). Therefore, there has been insufficient exploration of the molecular elements involved in these pathways in MC; careful analyses are needed in comparison to other cells such as macrophages, as well as among various MC subsets and between human and other MC.

Lipid Mediator Release

Activated MC release an abundance of arachidonic acid metabolites, notably leukotriene (LT) C₄, prostaglandin (PG) D₂, and platelet activating factor (PAF) (126–128). These lipid mediators have bronchoconstricting and vasoactive properties, but also participate in host defense, inflammation, and allergic diseases through diverse activities such as effector cell trafficking, antigen presentation, immune cell activation, and fibrosis (129–131). Eicosanoids, lipid mediators derived from arachidonic acid, are de novo synthesized and released immediately from activated cells rather than stored, and exert autocrine and paracrine functions. However, recent observations of intracellular localization of the PGD₂ receptor, DP2/CRTh2, suggest intracrine functions of this mediator (132, 133). Eicosanoid synthesis can occur at several sites in the cell, including the ER (134), nuclear membrane (134, 135), phagosomes (136), and cytoplasmic lipid bodies (Figure 1) (81, 82, 137, 138), and the site of synthesis likely depends on the cell type, as well as the nature of the stimulation [see review in Ref. (139)]. Whether the enzymes and other proteins needed for eicosanoid synthesis are de novo synthesized following cell activation, or are dispersed in the cell and then translocated to a site of synthesis following activation, are under debate. In either case, how these proteins are targeted to a specific intracellular compartment of eicosanoid synthesis is unknown.

Lipid bodies

Lipid bodies also referred to as lipid droplets are osmiophilic organelles surrounded by a monolayer of phospholipids and containing lipids with a unique fatty acid composition. Lipid bodies are composed of a core rich in neutral lipids and a variety of proteins depending upon the cell type and the conditions of stimulation (Figure 3) (137, 138, 140). These organelles are one of the major sites of eicosanoid generation. They are inducible during inflammatory processes and increase in size and number in several types of leukocytes, including MC (141–144). The numbers of lipid bodies in the cytoplasm of MC differ among MC phenotypes. For example, lipid bodies are rare in human skin MC in comparison to numbers in lung and gut MC (81, 82). In addition to eicosanoid synthesis, a few cytokines and chemokines are also found in lipid bodies of eosinophils (TNF), neutrophils (TNF), macrophages (TNF), and MC (TNF and bFGF) (33, 142). Much remains to be elucidated about the kinds of cytokines stored in lipid bodies, functions of these cytokines, and the mechanisms of their release.

Figure 3

Lipid body biogenesis

Although the details of the biogenesis of lipid bodies in MC are poorly understood, they bud from the ER membrane where neutral lipids are synthesized (Figure 3) (145). Lipid bodies can also increase in size by fusion and this process occurs in a rapid regulated way (146).

Mechanisms of synthesis and secretion of lipid mediators

Eicosanoids are made by oxidation of 20-carbon fatty acids. After activation, MC synthesize PGD₂ and LTC₄ from sequential enzymatic reactions of arachidonic acid metabolism of cyclooxygenase and lipoxygenase pathways, respectively. PAF also can be synthesized from lysophosphatidylcholine by PAF-acetyltransferase. Both arachidonic acid and lysophosphatidylcholine can be generated from membrane phospholipid (1-O-alkyl-2-arachidonoyl-sn-glycero-3-phosphocholine) by phospholipase A₂. Recently, studies on pro-resolving lipid mediators, such as resolvins, protectins, and maresins from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been advanced in macrophages and our understanding of their physiological, pathophysiological functions in resolution of inflammation are improved, but little is known their synthesis in MC (147).

Because eicosanoids synthesized intracellularly are negatively charged at physiological pH (148), they diffuse poorly across membranes. Thus, their secretion involves active transport through either organic anion transporters of the ATP-binding cassette type C family, also known as multidrug resistance-related proteins (149–152), or organic anion transporters of the solute carrier superfamily (153, 154). However, little is known of these mechanisms in MC and further study is needed to identify the mechanisms and their regulation.

Conclusion

Over several decades, there have been significant advances in our knowledge of MC biology that have transformed our understanding of this multifaceted immune cell from an effector cell in allergic inflammation to a major player in innate and acquired immunity. Because of the pivotal role of MC in allergic and other inflammatory reactions, therapeutic strategies to disrupt the action of MC mediators have been developed and used widely [e.g., anti-histamines, anti-IgE (omalizumab), and Cys-LT1 receptor antagonist (montelukast)]. However, there remain large gaps in our knowledge about intracellular trafficking of MC mediators, particularly in the selective mechanisms of storage and secretion that are often dependent on the specific stimuli involved. Our knowledge of the biogenesis of MC cargos, the heterogeneity of granules, and the molecules involved in trafficking pathways of mediator secretion are rapidly evolving and likely to be a productive in helping to unravel the complexities of MC biology. A greater understanding of mediator specific trafficking pathways will provide opportunities to develop novel therapeutic targets for the treatment of increasingly wide-spread allergic and other inflammatory diseases.

References

• 1

  MoonTCSt LaurentCDMorrisKEMarcetCYoshimuraTSekarYet alAdvances in mast cell biology: new understanding of heterogeneity and function. Mucosal Immunol (2010) 3(2):111–28.10.1038/mi.2009.136

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 2

  LancasterJRJr. A tutorial on the diffusibility and reactivity of free nitric oxide. Nitric Oxide (1997) 1(1):18–30.10.1006/niox.1996.0112

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 3

  LacyPStowJL. Cytokine release from innate immune cells: association with diverse membrane trafficking pathways. Blood (2011) 118(1):9–18.10.1182/blood-2010-08-265892

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 4

  MoriSSainoTSatohY. Effect of low temperatures on compound 48/80-induced intracellular Ca2+ changes and exocytosis of rat peritoneal mast cells. Arch Histol Cytol (2000) 63(3):261–70.10.1679/aohc.63.261

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 5

  SchickBAustenKF. Rat serosal mast cell degranulation mediated by chymase, an endogenous secretory granule protease: active site-dependent initiation at 1 degree C. J Immunol (1986) 136(10):3812–8.

  • Pubmed Abstract
  • Google Scholar

• 6

  AlfonsoACabadoAGVieytesMRBotanaLM. Calcium-pH crosstalks in rat mast cells: cytosolic alkalinization, but not intracellular calcium release, is a sufficient signal for degranulation. Br J Pharmacol (2000) 130(8):1809–16.10.1038/sj.bjp.0703490

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 7

  MullerKMeinekeV. Radiation-induced mast cell mediators differentially modulate chemokine release from dermal fibroblasts. J Dermatol Sci (2011) 61(3):199–205.10.1016/j.jdermsci.2011.01.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 8

  GullikssonMPalmbergLNilssonGAhlstedtSKumlinM. Release of prostaglandin D2 and leukotriene C4 in response to hyperosmolar stimulation of mast cells. Allergy (2006) 61(12):1473–9.10.1111/j.1398-9995.2006.01213.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 9

  WernerssonSPejlerG. Mast cell secretory granules: armed for battle. Nat Rev Immunol (2014) 14(7):478–94.10.1038/nri3690

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 10

  ChicoineEEstevePORobledoOVan ThemscheCPotworowskiEFSt-PierreY. Evidence for the role of promoter methylation in the regulation of MMP-9 gene expression. Biochem Biophys Res Commun (2002) 297(4):765–72.10.1016/S0006-291X(02)02283-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 11

  BurgoyneRDMorganA. Secretory granule exocytosis. Physiol Rev (2003) 83(2):581–632.10.1152/physrev.00031.2002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 12

  KarpG. Cell Biology. 6th ed. Hoboken: John Wiley & Sons Inc (2010).

  • Google Scholar

• 13

  SilverRBPappasGD. Secretion without membrane fusion: porocytosis. Anat Rec B New Anat (2005) 282(1):18–37.10.1002/ar.b.20050

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 14

  LorentzABaumannAVitteJBlankU. The SNARE machinery in mast cell secretion. Front Immunol (2012) 3:143.10.3389/fimmu.2012.00143

  • CrossRef
  • Google Scholar

• 15

  HammelILagunoffDGalliSJ. Regulation of secretory granule size by the precise generation and fusion of unit granules. J Cell Mol Med (2010) 14(7):1904–16.10.1111/j.1582-4934.2010.01071.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 16

  Carroll-PortilloASurviladzeZCambiALidkeDSWilsonBS. Mast cell synapses and exosomes: membrane contacts for information exchange. Front Immunol (2012) 3:46.10.3389/fimmu.2012.00046

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 17

  GalliSJTsaiM. IgE and mast cells in allergic disease. Nat Med (2012) 18(5):693–704.10.1038/nm.2755

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 18

  BenadoANasagi-AtiyaYSagi-EisenbergR. Protein trafficking in immune cells. Immunobiology (2009) 214(6):403–21.10.1016/j.imbio.2008.11.011

  • CrossRef
  • Google Scholar

• 19

  StowJLMurrayRZ. Intracellular trafficking and secretion of inflammatory cytokines. Cytokine Growth Factor Rev (2013) 24(3):227–39.10.1016/j.cytogfr.2013.04.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 20

  SchwartzLBLewisRASeldinDAustenKF. Acid hydrolases and tryptase from secretory granules of dispersed human lung mast cells. J Immunol (1981) 126(4):1290–4.

  • Pubmed Abstract
  • Google Scholar

• 21

  MillerJSWestinEHSchwartzLB. Cloning and characterization of complementary DNA for human tryptase. J Clin Invest (1989) 84(4):1188–95.10.1172/JCI114284

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22

  MillerJSMoxleyGSchwartzLB. Cloning and characterization of a second complementary DNA for human tryptase. J Clin Invest (1990) 86(3):864–70.10.1172/JCI114786

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 23

  VanderslicePBallingerSMTamEKGoldsteinSMCraikCSCaugheyGH. Human mast cell tryptase: multiple cDNAs and genes reveal a multigene serine protease family. Proc Natl Acad Sci U S A (1990) 87(10):3811–5.10.1073/pnas.87.10.3811

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 24

  WongGWTangYFeyfantESaliALiLLiYet alIdentification of a new member of the tryptase family of mouse and human mast cell proteases which possesses a novel COOH-terminal hydrophobic extension. J Biol Chem (1999) 274(43):30784–93.10.1074/jbc.274.43.30784

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 25

  CaugheyGHRaymondWWBlountJLHauLWPallaoroMWoltersPJet alCharacterization of human gamma-tryptases, novel members of the chromosome 16p mast cell tryptase and prostasin gene families. J Immunol (2000) 164(12):6566–75.10.4049/jimmunol.164.12.6566

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 26

  WangHWMcNeilHPHusainALiuKTedlaNThomasPSet alDelta tryptase is expressed in multiple human tissues, and a recombinant form has proteolytic activity. J Immunol (2002) 169(9):5145–52.10.4049/jimmunol.169.9.5145

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 27

  WongGWFosterPSYasudaSQiJCMahalingamSMellorEAet alBiochemical and functional characterization of human transmembrane tryptase (TMT)/tryptase gamma. TMT is an exocytosed mast cell protease that induces airway hyperresponsiveness in vivo via an interleukin-13/interleukin-4 receptor alpha/signal transducer and activator of transcription (STAT) 6-dependent pathway. J Biol Chem (2002) 277(44):41906–15.10.1074/jbc.M205868200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 28

  SchwartzLBIraniAMRollerKCastellsMCSchechterNM. Quantitation of histamine, tryptase, and chymase in dispersed human T and TC mast cells. J Immunol (1987) 138(8):2611–5.

  • Pubmed Abstract
  • Google Scholar

• 29

  PejlerGKnightSDHenningssonFWernerssonS. Novel insights into the biological function of mast cell carboxypeptidase A. Trends Immunol (2009) 30(8):401–8.10.1016/j.it.2009.04.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 30

  SchechterNMWangZMBlacherRWLessinSRLazarusGSRubinH. Determination of the primary structures of human skin chymase and cathepsin G from cutaneous mast cells of urticaria pigmentosa lesions. J Immunol (1994) 152(8):4062–9.

  • Pubmed Abstract
  • Google Scholar

• 31

  StrikMCde KoningPJKleijmeerMJBladergroenBAWolbinkAMGriffithJMet alHuman mast cells produce and release the cytotoxic lymphocyte associated protease granzyme B upon activation. Mol Immunol (2007) 44(14):3462–72.10.1016/j.molimm.2007.03.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32

  OlszewskiMBGrootAJDastychJKnolEF. TNF trafficking to human mast cell granules: mature chain-dependent endocytosis. J Immunol (2007) 178(9):5701–9.10.4049/jimmunol.178.9.5701

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 33

  DvorakAMMorganESWellerPF. Ultrastructural immunolocalization of basic fibroblast growth factor to lipid bodies and secretory granules in human mast cells. Histochem J (2001) 33(7):397–402.10.1023/A:1013771827069

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 34

  WilsonSJShuteJKHolgateSTHowarthPHBraddingP. Localization of interleukin (IL) -4 but not IL-5 to human mast cell secretory granules by immunoelectron microscopy. Clin Exp Allergy (2000) 30(4):493–500.10.1046/j.1365-2222.2000.00756.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 35

  de PaulisAMinopoliGArbustiniEde CrescenzoGDal PiazFPucciPet alStem cell factor is localized in, released from, and cleaved by human mast cells. J Immunol (1999) 163(5):2799–808.

  • Pubmed Abstract
  • Google Scholar

• 36

  StevensRLFoxCCLichtensteinLMAustenKF. Identification of chondroitin sulfate E proteoglycans and heparin proteoglycans in the secretory granules of human lung mast cells. Proc Natl Acad Sci U S A (1988) 85(7):2284–7.10.1073/pnas.85.7.2284

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 37

  MetcalfeDDLewisRASilbertJERosenbergRDWassermanSIAustenKF. Isolation and characterization of heparin from human lung. J Clin Invest (1979) 64(6):1537–43.10.1172/JCI109613

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 38

  UvnasB. Recent observations on mechanisms of storage and release of mast cell histamine. Applicability to other biogenic amines. Agents Actions Suppl (1992) 36:23–33.

  • Google Scholar

• 39

  HoganADSchwartzLB. Markers of mast cell degranulation. Methods (1997) 13(1):43–52.10.1006/meth.1997.0494

  • CrossRef
  • Google Scholar

• 40

  HohmanRJDreskinSC. Measuring degranulation of mast cells. Curr Protoc Immunol (2001) Chapter 7:Unit726.10.1002/0471142735.im0726s08

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41

  DouaiherJSuccarJLancerottoLGurishMFOrgillDPHamiltonMJet alDevelopment of mast cells and importance of their tryptase and chymase serine proteases in inflammation and wound healing. Adv Immunol (2014) 122:211–52.10.1016/B978-0-12-800267-4.00006-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42

  BaramDAdachiRMedaliaOTuvimMDickeyBFMekoriYAet alSynaptotagmin II negatively regulates Ca2+-triggered exocytosis of lysosomes in mast cells. J Exp Med (1999) 189(10):1649–58.10.1084/jem.189.10.1649

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43

  RaposoGTenzaDMecheriSPeronetRBonnerotCDesaymardC. Accumulation of major histocompatibility complex class II molecules in mast cell secretory granules and their release upon degranulation. Mol Biol Cell (1997) 8(12):2631–45.10.1091/mbc.8.12.2631

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44

  PuriNRochePA. Mast cells possess distinct secretory granule subsets whose exocytosis is regulated by different SNARE isoforms. Proc Natl Acad Sci U S A (2008) 105(7):2580–5.10.1073/pnas.0707854105

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 45

  GuninAGKornilovaNKVasilievaOVPetrovVV. Age-related changes in proliferation, the numbers of mast cells, eosinophils, and CD45-positive cells in human dermis. J Gerontol A Biol Sci Med Sci (2011) 66(4):385–92.10.1093/gerona/glq205

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 46

  HammelIDvorakAMPetersSPSchulmanESDvorakHFLichtensteinLMet alDifferences in the volume distributions of human lung mast cell granules and lipid bodies: evidence that the size of these organelles is regulated by distinct mechanisms. J Cell Biol (1985) 100(5):1488–92.10.1083/jcb.100.5.1488

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 47

  RiedelDAntoninWFernandez-ChaconRAlvarez de ToledoGJoTGeppertMet alRab3D is not required for exocrine exocytosis but for maintenance of normally sized secretory granules. Mol Cell Biol (2002) 22(18):6487–97.10.1128/MCB.22.18.6487-6497.2002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48

  AzouzNPZurNEferganAOhbayashiNFukudaMAmihaiDet alRab5 is a novel regulator of mast cell secretory granules: impact on size, cargo, and exocytosis. J Immunol (2014) 192(9):4043–53.10.4049/jimmunol.1302196

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 49

  DurchfortNVerhoefSVaughnMBShresthaRAdamDKaplanJet alThe enlarged lysosomes in beige j cells result from decreased lysosome fission and not increased lysosome fusion. Traffic (2012) 13(1):108–19.10.1111/j.1600-0854.2011.01300.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50

  GrimbergEPengZHammelISagi-EisenbergR. Synaptotagmin III is a critical factor for the formation of the perinuclear endocytic recycling compartment and determination of secretory granules size. J Cell Sci (2003) 116(Pt 1):145–54.10.1242/jcs.00186

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 51

  PrasadPYanagiharaAASmall-HowardALTurnerHStokesAJ. Secretogranin III directs secretory vesicle biogenesis in mast cells in a manner dependent upon interaction with chromogranin A. J Immunol (2008) 181(7):5024–34.10.4049/jimmunol.181.7.5024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 52

  HenningssonFHergethSCorteliusRAbrinkMPejlerG. A role for serglycin proteoglycan in granular retention and processing of mast cell secretory granule components. FEBS J (2006) 273(21):4901–12.10.1111/j.1742-4658.2006.05489.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53

  MeloFRWaernIRonnbergEAbrinkMLeeDMSchlennerSMet alA role for serglycin proteoglycan in mast cell apoptosis induced by a secretory granule-mediated pathway. J Biol Chem (2011) 286(7):5423–33.10.1074/jbc.M110.176461

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 54

  NakazawaSSakanakaMFurutaKNatsuharaMTakanoHTsuchiyaSet alHistamine synthesis is required for granule maturation in murine mast cells. Eur J Immunol (2014) 44(1):204–14.10.1002/eji.201343838

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55

  DorayBKornfeldS. Gamma subunit of the AP-1 adaptor complex binds clathrin: implications for cooperative binding in coated vesicle assembly. Mol Biol Cell (2001) 12(7):1925–35.10.1091/mbc.12.7.1925

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 56

  BonnemaisonMLEipperBAMainsRE. Role of adaptor proteins in secretory granule biogenesis and maturation. Front Endocrinol (2013) 4:101.10.3389/fendo.2013.00101

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57

  LagunoffD. Analysis of dye binding sites in mast cell granules. Biochemistry (1974) 13(19):3982–6.10.1021/bi00716a025

  • CrossRef
  • Google Scholar

• 58

  NitzanyEHammelIMeilijsonI. Quantal basis of vesicle growth and information content, a unified approach. J Theor Biol (2010) 266(1):202–9.10.1016/j.jtbi.2010.06.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59

  ChinWCOrellanaMVQuesadaIVerdugoP. Secretion in unicellular marine phytoplankton: demonstration of regulated exocytosis in Phaeocystis globosa. Plant Cell Physiol (2004) 45(5):535–42.10.1093/pcp/pch062

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60

  RonnbergEMeloFRPejlerG. Mast cell proteoglycans. J Histochem Cytochem (2012) 60(12):950–62.10.1369/0022155412458927

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61

  IkeyaMYamanoueKMochizukiYKonishiHTadokoroSTanakaMet alOrai-2 is localized on secretory granules and regulates antigen-evoked Ca2+ mobilization and exocytosis in mast cells. Biochem Biophys Res Commun (2014) 451(1):62–7.10.1016/j.bbrc.2014.07.060

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  MelicoffESansores-GarciaLGomezAMoreiraDCDattaPThakurPet alSynaptotagmin-2 controls regulated exocytosis but not other secretory responses of mast cells. J Biol Chem (2009) 284(29):19445–51.10.1074/jbc.M109.002550

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63

  BiederbickALichtAKleeneR. Serglycin proteoglycan is sorted into zymogen granules of rat pancreatic acinar cells. Eur J Cell Biol (2003) 82(1):19–29.10.1078/0171-9335-00287

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64

  MerickelAEdwardsRH. Transport of histamine by vesicular monoamine transporter-2. Neuropharmacology (1995) 34(11):1543–7.10.1016/0028-3908(95)00148-Y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65

  TravisERWangYMMichaelDJCaronMGWightmanRM. Differential quantal release of histamine and 5-hydroxytryptamine from mast cells of vesicular monoamine transporter 2 knockout mice. Proc Natl Acad Sci U S A (2000) 97(1):162–7.10.1073/pnas.97.1.162

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 66

  RingvallMRonnbergEWernerssonSDuelliAHenningssonFAbrinkMet alSerotonin and histamine storage in mast cell secretory granules is dependent on serglycin proteoglycan. J Allergy Clin Immunol (2008) 121(4):1020–6.10.1016/j.jaci.2007.11.031

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67

  HumphriesDEWongGWFriendDSGurishMFQiuWTHuangCet alHeparin is essential for the storage of specific granule proteases in mast cells. Nature (1999) 400(6746):769–72.10.1038/23481

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68

  UvnasBAborgCHBergendorffA. Storage of histamine in mast cells. Evidence for an ionic binding of histamine to protein carboxyls in the granule heparin-protein complex. Acta Physiol Scand Suppl (1970) 336:1–26.

  • Google Scholar

• 69

  RabensteinDLBrattPPengJ. Quantitative characterization of the binding of histamine by heparin. Biochemistry (1998) 37(40):14121–7.10.1021/bi980625y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70

  BergendorffAUvnasB. Storage of 5-hydroxytryptamine in rat mast cells. Evidence for an ionic binding to carboxyl groups in a granule heparin-protein complex. Acta Physiol Scand (1972) 84(3):320–31.10.1111/j.1748-1716.1972.tb05183.x

  • CrossRef
  • Google Scholar

• 71

  Garcia-FaroldiGRodriguezCEUrdialesJLPerez-PomaresJMDavilaJCPejlerGet alPolyamines are present in mast cell secretory granules and are important for granule homeostasis. PLoS One (2010) 5(11):11.10.1371/journal.pone.0015071

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72

  OlszewskiMBTrzaskaDKnolEFAdamczewskaVDastychJ. Efficient sorting of TNF-alpha to rodent mast cell granules is dependent on N-linked glycosylation. Eur J Immunol (2006) 36(4):997–1008.10.1002/eji.200535323

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  BenyonRCBissonnetteEYBefusAD. Tumor necrosis factor-alpha dependent cytotoxicity of human skin mast cells is enhanced by anti-IgE antibodies. J Immunol (1991) 147(7):2253–8.

  • Pubmed Abstract
  • Google Scholar

• 74

  GordonJRGalliSJ. Mast cells as a source of both preformed and immunologically inducible TNF-alpha/cachectin. Nature (1990) 346(6281):274–6.10.1038/346274a0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 75

  OkayamaYKobayashiHAshmanLKDobashiKNakazawaTHolgateSTet alHuman lung mast cells are enriched in the capacity to produce granulocyte-macrophage colony-stimulating factor in response to IgE-dependent stimulation. Eur J Immunol (1998) 28(2):708–15.10.1002/(SICI)1521-4141(199802)28:02<708::AID-IMMU708>3.0.CO;2-A

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76

  VoehringerD. Protective and pathological roles of mast cells and basophils. Nat Rev Immunol (2013) 13(5):362–75.10.1038/nri3427

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77

  MoscatelliD. High and low affinity binding sites for basic fibroblast growth factor on cultured cells: absence of a role for low affinity binding in the stimulation of plasminogen activator production by bovine capillary endothelial cells. J Cell Physiol (1987) 131(1):123–30.10.1002/jcp.1041310118

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78

  DvorakAMMcLeodRSOnderdonkAMonahan-EarleyRACullenJBAntonioliDAet alUltrastructural evidence for piecemeal and anaphylactic degranulation of human gut mucosal mast cells in vivo. Int Arch Allergy Immunol (1992) 99(1):74–83.10.1159/000236338

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79

  DvorakAMMorganES. Diamine oxidase-gold enzyme-affinity ultrastructural demonstration that human gut mucosal mast cells secrete histamine by piecemeal degranulation in vivo. J Allergy Clin Immunol (1997) 99(6 Pt 1):812–20.10.1016/S0091-6749(97)80016-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80

  EbiharaNWatanabeYMurakamiA. The ultramicrostructure of secretory granules of mast cells in giant papillae of vernal keratoconjunctivitis patients. Nihon Ganka Gakkai Zasshi (2008) 112(7):581–9.

  • Pubmed Abstract
  • Google Scholar

• 81

  DvorakAMMasseyWWarnerJKissellSKagey-SobotkaALichtensteinLM. IgE-mediated anaphylactic degranulation of isolated human skin mast cells. Blood (1991) 77(3):569–78.

  • Pubmed Abstract
  • Google Scholar

• 82

  DvorakAMKissellS. Granule changes of human skin mast cells characteristic of piecemeal degranulation and associated with recovery during wound healing in situ. J Leukoc Biol (1991) 49(2):197–210.

  • Pubmed Abstract
  • Google Scholar

• 83

  DvorakAMTepperRIWellerPFMorganESEstrellaPMonahan-EarleyRAet alPiecemeal degranulation of mast cells in the inflammatory eyelid lesions of interleukin-4 transgenic mice. Evidence of mast cell histamine release in vivo by diamine oxidase-gold enzyme-affinity ultrastructural cytochemistry. Blood (1994) 83(12):3600–12.

  • Pubmed Abstract
  • Google Scholar

• 84

  ChyczewskiLDebekWChyczewskaEDebekKBankowskiE. Morphology of lung mast cells in rats treated with bleomycin. Exp Toxicol Pathol (1996) 48(6):515–7.10.1016/S0940-2993(96)80070-4

  • CrossRef
  • Google Scholar

• 85

  VicarioMGuilarteMAlonsoCYangPMartinezCRamosLet alChronological assessment of mast cell-mediated gut dysfunction and mucosal inflammation in a rat model of chronic psychosocial stress. Brain Behav Immun (2010) 24(7):1166–75.10.1016/j.bbi.2010.06.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86

  YanXJFengCCLiuQZhangLYDongXLiuZLet alVagal afferents mediate antinociception of estrogen in a rat model of visceral pain: the involvement of intestinal mucosal mast cells and 5-hydroxytryptamine 3 signaling. J Pain (2014) 15(2):204–17.10.1016/j.jpain.2013.10.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87

  IwamotoSAsadaYEbiharaNHoriKOkayamaYKashiwakuraJet alInteraction between conjunctival epithelial cells and mast cells induces CCL2 expression and piecemeal degranulation in mast cells. Invest Ophthalmol Vis Sci (2013) 54(4):2465–73.10.1167/iovs.12-10664

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 88

  McCurdyJDOlynychTJMaherLHMarshallJS. Cutting edge: distinct Toll-like receptor 2 activators selectively induce different classes of mediator production from human mast cells. J Immunol (2003) 170(4):1625–9.10.4049/jimmunol.170.4.1625

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89

  FrossiBD’IncaFCrivellatoESibilanoRGriGMongilloMet alSingle-cell dynamics of mast cell-CD4+ CD25+ regulatory T cell interactions. Eur J Immunol (2011) 41(7):1872–82.10.1002/eji.201041300

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90

  CrivellatoENicoBGalloVPRibattiD. Cell secretion mediated by granule-associated vesicle transport: a glimpse at evolution. Anat Rec (2010) 293(7):1115–24.10.1002/ar.21146

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91

  WoskaJRJr.GillespieME. SNARE complex-mediated degranulation in mast cells. J Cell Mol Med (2012) 16(4):649–56.10.1111/j.1582-4934.2011.01443.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  SanderLEFrankSPBolatSBlankUGalliTBigalkeHet alVesicle associated membrane protein (VAMP)-7 and VAMP-8, but not VAMP-2 or VAMP-3, are required for activation-induced degranulation of mature human mast cells. Eur J Immunol (2008) 38(3):855–63.10.1002/eji.200737634

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93

  GoishiKMizunoKNakanishiHSasakiT. Involvement of Rab27 in antigen-induced histamine release from rat basophilic leukemia 2H3 cells. Biochem Biophys Res Commun (2004) 324(1):294–301.10.1016/j.bbrc.2004.09.050

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94

  Martin-VerdeauxSPomboIIannascoliBRoaMVarin-BlankNRiveraJet alEvidence of a role for Munc18-2 and microtubules in mast cell granule exocytosis. J Cell Sci (2003) 116(Pt 2):325–34.10.1242/jcs.00216

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95

  TadokoroSKurimotoTNakanishiMHirashimaN. Munc18-2 regulates exocytotic membrane fusion positively interacting with syntaxin-3 in RBL-2H3 cells. Mol Immunol (2007) 44(13):3427–33.10.1016/j.molimm.2007.02.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96

  TadokoroSNakanishiMHirashimaN. Complexin II facilitates exocytotic release in mast cells by enhancing Ca2+ sensitivity of the fusion process. J Cell Sci (2005) 118(Pt 10):2239–46.10.1242/jcs.02338

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 97

  HammelIMeilijsonI. The stealthy nano-machine behind mast cell granule size distribution. Mol Immunol (2015) 63(1):45–54.10.1016/j.molimm.2014.02.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98

  JenaBP. Secretory vesicles transiently dock and fuse at the porosome to discharge contents during cell secretion. Cell Biol Int (2010) 34(1):3–12.10.1042/CBI20090161

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99

  BaramDPengZMedaliaOMekoriYASagi-EisenbergR. Synaptotagmin II negatively regulates MHC class II presentation by mast cells. Mol Immunol (2002) 38(16-18):1347–52.10.1016/S0161-5890(02)00086-X

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100

  HabermanYZivIGorzalczanyYHirschbergKMittlemanLFukudaMet alSynaptotagmin (Syt) IX is an essential determinant for protein sorting to secretory granules in mast cells. Blood (2007) 109(8):3385–92.10.1182/blood-2006-07-033126

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101

  RoaMPaumetFLe MaoJDavidBBlankU. Involvement of the ras-like GTPase rab3d in RBL-2H3 mast cell exocytosis following stimulation via high affinity IgE receptors (Fc epsilonRI). J Immunol (1997) 159(6):2815–23.

  • Pubmed Abstract
  • Google Scholar

• 102

  SmithJThompsonNThompsonJArmstrongJHayesBCroftsAet alRat basophilic leukaemia (RBL) cells overexpressing Rab3a have a reversible block in antigen-stimulated exocytosis. Biochem J (1997) 323(Pt 2):321–8.

  • Pubmed Abstract
  • Google Scholar

• 103

  TuvimMJAdachiRChocanoJFMooreRHLampertRMZeraEet alRab3D, a small GTPase, is localized on mast cell secretory granules and translocates to the plasma membrane upon exocytosis. Am J Respir Cell Mol Biol (1999) 20(1):79–89.10.1165/ajrcmb.20.1.3279

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104

  ElstakEDNeeftMNehmeNTVoortmanJCheungMGoodarzifardMet alThe munc13-4-rab27 complex is specifically required for tethering secretory lysosomes at the plasma membrane. Blood (2011) 118(6):1570–8.10.1182/blood-2011-02-339523

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105

  SinghRKMizunoKWasmeierCWavre-ShaptonSTRecchiCCatzSDet alDistinct and opposing roles for Rab27a/Mlph/MyoVa and Rab27b/Munc13-4 in mast cell secretion. FEBS J (2013) 280(3):892–903.10.1111/febs.12081

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106

  MizunoKTolmachovaTUshakovDSRomaoMAbrinkMFerencziMAet alRab27b regulates mast cell granule dynamics and secretion. Traffic (2007) 8(7):883–92.10.1111/j.1600-0854.2007.00571.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107

  Hong-GellerECerioneRA. Cdc42 and Rac stimulate exocytosis of secretory granules by activating the IP3/calcium pathway in RBL-2H3 mast cells. J Cell Biol (2000) 148(3):481–94.10.1083/jcb.148.3.481

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108

  Hong-GellerEHolowkaDSiraganianRPBairdBCerioneRA. Activated Cdc42/Rac reconstitutes Fcepsilon RI-mediated Ca2+ mobilization and degranulation in mutant RBL mast cells. Proc Natl Acad Sci U S A (2001) 98(3):1154–9.10.1073/pnas.98.3.1154

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 109

  BaierANdohVNLacyPEitzenG. Rac1 and Rac2 control distinct events during antigen-stimulated mast cell exocytosis. J Leukoc Biol (2014) 95:763–74.10.1189/jlb.0513281

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110

  OgawaKTanakaYUrunoTDuanXHaradaYSanematsuFet alDOCK5 functions as a key signaling adaptor that links FcepsilonRI signals to microtubule dynamics during mast cell degranulation. J Exp Med (2014) 211(7):1407–19.10.1084/jem.20131926

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111

  HaddockBJZhuYDoyleSPAbdullahLHDavisCW. Role of MARCKS in regulated secretion from mast cells and airway goblet cells. Am J Physiol Lung Cell Mol Physiol (2014) 306(10):L925–36.10.1152/ajplung.00213.2013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  BondLMPedenAAKendrick-JonesJSellersJRBussF. Myosin VI and its binding partner optineurin are involved in secretory vesicle fusion at the plasma membrane. Mol Biol Cell (2011) 22(1):54–65.10.1091/mbc.E10-06-0553

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113

  FahrnerMDerlerIJardinIRomaninC. The STIM1/Orai signaling machinery. Channels (2013) 7(5):330–43.10.4161/chan.26742

  • CrossRef
  • Google Scholar

• 114

  AshmoleIBraddingP. Ion channels regulating mast cell biology. Clin Exp Allergy (2013) 43(5):491–502.10.1111/cea.12043

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115

  InohYTadokoroSTanabeHInoueMHirashimaNNakanishiMet alInhibitory effects of a cationic liposome on allergic reaction mediated by mast cell activation. Biochem Pharmacol (2013) 86(12):1731–8.10.1016/j.bcp.2013.09.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116

  MaHTBeavenMA. Regulators of Ca(2+) signaling in mast cells: potential targets for treatment of mast cell-related diseases?Adv Exp Med Biol (2011) 716:62–90.10.1007/978-1-4419-9533-9_5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117

  UshioHUenoTKojimaYKomatsuMTanakaSYamamotoAet alCrucial role for autophagy in degranulation of mast cells. J Allergy Clin Immunol (2011) 127(5):1267–76e6.10.1016/j.jaci.2010.12.1078

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 118

  KowalJTkachMTheryC. Biogenesis and secretion of exosomes. Curr Opin Cell Biol (2014) 29C:116–25.10.1016/j.ceb.2014.05.004

  • CrossRef
  • Google Scholar

• 119

  ValadiHEkstromKBossiosASjostrandMLeeJJLotvallJO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol (2007) 9(6):654–9.10.1038/ncb1596

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120

  EkstromKValadiHSjostrandMMalmhallCBossiosAEldhMet alCharacterization of mRNA and microRNA in human mast cell-derived exosomes and their transfer to other mast cells and blood CD34 progenitor cells. J Extracell Vesicles (2012) 1:18389.10.3402/jev.v1i0.18389

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121

  SkokosDBotrosHGDemeureCMorinJPeronetRBirkenmeierGet alMast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo. J Immunol (2003) 170(6):3037–45.10.4049/jimmunol.170.6.3037

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122

  MerluzziSBettoECeccaroniAAMagrisRGiuntaMMionF. Mast cells, basophils and B cell connection network. Mol Immunol (2015) 63(1):94–103.10.1016/j.molimm.2014.02.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123

  Villarroya-BeltriCBaixauliFGutierrez-VazquezCSanchez-MadridFMittelbrunnM. Sorting it out: regulation of exosome loading. Semin Cancer Biol (2014) 28C:3–13.10.1016/j.semcancer.2014.04.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124

  FrankSPThonKPBischoffSCLorentzA. SNAP-23 and syntaxin-3 are required for chemokine release by mature human mast cells. Mol Immunol (2011) 49(1-2):353–8.10.1016/j.molimm.2011.09.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 125

  TiwariNWangCCBrochettaCKeGVitaFQiZet alVAMP-8 segregates mast cell-preformed mediator exocytosis from cytokine trafficking pathways. Blood (2008) 111(7):3665–74.10.1182/blood-2007-07-103309

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126

  HogaboamCMDonigi-GaleDShoupeTSBissonnetteEYBefusADWallaceJL. Platelet-activating factor synthesis by peritoneal mast cells and its inhibition by two quinoline-based compounds. Br J Pharmacol (1992) 105(1):87–92.10.1111/j.1476-5381.1992.tb14215.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127

  Mencia-HuertaJMLewisRARazinEAustenKF. Antigen-initiated release of platelet-activating factor (PAF-acether) from mouse bone marrow-derived mast cells sensitized with monoclonal IgE. J Immunol (1983) 131(6):2958–64.

  • Pubmed Abstract
  • Google Scholar

• 128

  SchleimerRPDavidsonDALichtensteinLMAdkinsonNFJr. Selective inhibition of arachidonic acid metabolite release from human lung tissue by antiinflammatory steroids. J Immunol (1986) 136(8):3006–11.

  • Pubmed Abstract
  • Google Scholar

• 129

  BoyceJA. Eicosanoid mediators of mast cells: receptors, regulation of synthesis, and pathobiologic implications. Chem Immunol Allergy (2005) 87:59–79.10.1159/000087571

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 130

  Peters-GoldenMCanettiCMancusoPCoffeyMJ. Leukotrienes: underappreciated mediators of innate immune responses. J Immunol (2005) 174(2):589–94.10.4049/jimmunol.174.2.589

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 131

  JooMSadikotRT. PGD synthase and PGD2 in immune response. Mediators Inflamm (2012) 2012:503128.10.1155/2012/503128

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132

  MoonTCCampos-AlbertoEYoshimuraTBredoGRiegerAMPuttaguntaLet alExpression of DP2 (CRTh2), a prostaglandin D2 receptor, in human mast cells. PLoS One (2014) 9(9):e108595.10.1371/journal.pone.0108595

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133

  BindaCGenierSCartierALarriveeJFStankovaJYoungJCet alA G protein-coupled receptor and the intracellular synthase of its agonist functionally cooperate. J Cell Biol (2014) 204(3):377–93.10.1083/jcb.201304015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 134

  BrockTGMcNishRWPeters-GoldenM. Capacity for repeatable leukotriene generation after transient stimulation of mast cells and macrophages. Biochem J (1998) 329(Pt 3):519–25.

  • Pubmed Abstract
  • Google Scholar

• 135

  BrockTGMcNishRWPeters-GoldenM. Translocation and leukotriene synthetic capacity of nuclear 5-lipoxygenase in rat basophilic leukemia cells and alveolar macrophages. J Biol Chem (1995) 270(37):21652–8.10.1074/jbc.270.37.21652

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136

  BalestrieriBHsuVWGilbertHLeslieCCHanWKBonventreJVet alGroup V secretory phospholipase A2 translocates to the phagosome after zymosan stimulation of mouse peritoneal macrophages and regulates phagocytosis. J Biol Chem (2006) 281(10):6691–8.10.1074/jbc.M508314200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 137

  DvorakAMDvorakHFPetersSPShulmanESMacGlashanDWJr.PyneKet alLipid bodies: cytoplasmic organelles important to arachidonate metabolism in macrophages and mast cells. J Immunol (1983) 131(6):2965–76.

  • Pubmed Abstract
  • Google Scholar

• 138

  PachecoPBozzaFAGomesRNBozzaMWellerPFCastro-Faria-NetoHCet alLipopolysaccharide-induced leukocyte lipid body formation in vivo: innate immunity elicited intracellular Loci involved in eicosanoid metabolism. J Immunol (2002) 169(11):6498–506.10.4049/jimmunol.169.11.6498

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 139

  BozzaPTBakker-AbreuINavarro-XavierRABandeira-MeloC. Lipid body function in eicosanoid synthesis: an update. Prostaglandins Leukot Essent Fatty Acids (2011) 85(5):205–13.10.1016/j.plefa.2011.04.020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 140

  ThiamARFareseRVJr.WaltherTC. The biophysics and cell biology of lipid droplets. Nat Rev Mol Cell Biol (2013) 14(12):775–86.10.1038/nrm3699

  • CrossRef
  • Google Scholar

• 141

  BozzaPTYuWCassaraJWellerPF. Pathways for eosinophil lipid body induction: differing signal transduction in cells from normal and hypereosinophilic subjects. J Leukoc Biol (1998) 64(4):563–9.

  • Pubmed Abstract
  • Google Scholar

• 142

  BeilWJWellerPFPeppercornMAGalliSJDvorakAM. Ultrastructural immunogold localization of subcellular sites of TNF-alpha in colonic Crohn’s disease. J Leukoc Biol (1995) 58(3):284–98.

  • Pubmed Abstract
  • Google Scholar

• 143

  ReginatoAJSchumacherHRAllanDARabinowitzJL. Acute monoarthritis associated with lipid liquid crystals. Ann Rheum Dis (1985) 44(8):537–43.10.1136/ard.44.8.537

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 144

  DichlbergerAKovanenPTSchneiderWJ. Mast cells: from lipid droplets to lipid mediators. Clin Sci (2013) 125(3):121–30.10.1042/CS20120602

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 145

  WilflingFHaasJTWaltherTCFareseRVJr. Lipid droplet biogenesis. Curr Opin Cell Biol (2014) 29C:39–45.10.1016/j.ceb.2014.03.008

  • CrossRef
  • Google Scholar

• 146

  BozzaPTBandeira-MeloC. Mechanisms of leukocyte lipid body formation and function in inflammation. Mem Inst Oswaldo Cruz (2005) 100(Suppl 1):113–20.10.1590/S0074-02762005000900020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 147

  SerhanCN. Pro-resolving lipid mediators are leads for resolution physiology. Nature (2014) 510(7503):92–101.10.1038/nature13479

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 148

  ChanBSSatrianoJAPucciMSchusterVL. Mechanism of prostaglandin E2 transport across the plasma membrane of HeLa cells and Xenopus oocytes expressing the prostaglandin transporter "PGT". J Biol Chem (1998) 273(12):6689–97.10.1074/jbc.273.12.6689

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 149

  JedlitschkyGKepplerD. Transport of leukotriene C4 and structurally related conjugates. Vitam Horm (2002) 64:153–84.10.1016/S0083-6729(02)64005-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150

  RiusMHummel-EisenbeissJKepplerD. ATP-dependent transport of leukotrienes B4 and C4 by the multidrug resistance protein ABCC4 (MRP4). J Pharmacol Exp Ther (2008) 324(1):86–94.10.1124/jpet.107.131342

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151

  ReidGWielingaPZelcerNvan der HeijdenIKuilAde HaasMet alThe human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A (2003) 100(16):9244–9.10.1073/pnas.1033060100

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 152

  LinZPZhuYLJohnsonDRRiceKPNottoliTHainsBCet alDisruption of cAMP and prostaglandin E2 transport by multidrug resistance protein 4 deficiency alters cAMP-mediated signaling and nociceptive response. Mol Pharmacol (2008) 73(1):243–51.10.1124/mol.107.039594

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 153

  AdachiHSuzukiTAbeMAsanoNMizutamariHTanemotoMet alMolecular characterization of human and rat organic anion transporter OATP-D. Am J Physiol Renal Physiol (2003) 285(6):F1188–97.10.1152/ajprenal.00402.2002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 154

  NishioTAdachiHNakagomiRTokuiTSatoETanemotoMet alMolecular identification of a rat novel organic anion transporter moat1, which transports prostaglandin D2, leukotriene C4, and taurocholate. Biochem Biophys Res Commun (2000) 275(3):831–8.10.1006/bbrc.2000.3377

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 155

  BurdPRRogersHWGordonJRMartinCAJayaramanSWilsonSDet alInterleukin 3-dependent and -independent mast cells stimulated with IgE and antigen express multiple cytokines. J Exp Med (1989) 170(1):245–57.10.1084/jem.170.1.245

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 156

  LewisRASoterNADiamondPTAustenKFOatesJARobertsLJII. Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE. J Immunol (1982) 129(4):1627–31.

  • Pubmed Abstract
  • Google Scholar

• 157

  MacDonaldAJPickJBissonnetteEYBefusAD. Rat mucosal mast cells: the cultured bone marrow-derived mast cell is biochemically and functionally analogous to its counterpart in vivo. Immunology (1998) 93(4):533–9.10.1046/j.1365-2567.1998.00465.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 158

  GilchristMMcCauleySDBefusAD. Expression, localization, and regulation of NOS in human mast cell lines: effects on leukotriene production. Blood (2004) 104(2):462–9.10.1182/blood-2003-08-2990

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 159

  MoonTCYoshimuraTParsonsTBefusAD. Microenvironmental regulation of inducible nitric oxide synthase expression and nitric oxide production in mouse bone marrow-derived mast cells. J Leukoc Biol (2012) 91(4):581–90.10.1189/jlb.0811436

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 160

  SwindleEJMetcalfeDDColemanJW. Rodent and human mast cells produce functionally significant intracellular reactive oxygen species but not nitric oxide. J Biol Chem (2004) 279(47):48751–9.10.1074/jbc.M409738200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 161

  WangXSSze WingSKwok HoYLauHY. Functional characterization of human mast cells cultured from adult peripheral blood. Int Immunopharmacol (2006) 6(5):839–47.10.1016/j.intimp.2005.12.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 162

  KulkaMSheenCHTancownyBPGrammerLCSchleimerRP. Neuropeptides activate human mast cell degranulation and chemokine production. Immunology (2008) 123(3):398–410.10.1111/j.1365-2567.2007.02705.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 163

  KarimiKKoolMNijkampFPRedegeldFA. Substance P can stimulate prostaglandin D(2) and leukotriene C(4) generation without granule exocytosis in murine mast cells. Eur J Pharmacol (2004) 489(1-2):49–54.10.1016/j.ejphar.2004.03.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 164

  OgasawaraTMurakamiMSuzuki-NishimuraTUchidaMKKudoI. Mouse bone marrow-derived mast cells undergo exocytosis, prostanoid generation, and cytokine expression in response to G protein-activating polybasic compounds after coculture with fibroblasts in the presence of c-kit ligand. J Immunol (1997) 158(1):393–404.

  • Pubmed Abstract
  • Google Scholar

• 165

  Reynier-RebuffelAMMathiauPCallebertJDimitriadouVFarjaudonNKacemKet alSubstance P, calcitonin gene-related peptide, and capsaicin release serotonin from cerebrovascular mast cells. Am J Physiol (1994) 267(5 Pt 2):R1421–9.

  • Pubmed Abstract
  • Google Scholar

• 166

  McNeilBDPundirPHanLMeekerSUndemBJKulkaMet alIdentification of the receptor for mast cell basic secretagogues and its critical role in pseudo-allergic drug reactions. Nature (2014) (in press).

  • Google Scholar

• 167

  NiyonsabaFSomeyaAHirataMOgawaHNagaokaI. Evaluation of the effects of peptide antibiotics human beta-defensins-1/-2 and LL-37 on histamine release and prostaglandin D(2) production from mast cells. Eur J Immunol (2001) 31(4):1066–75.10.1002/1521-4141(200104)31:4<1066::AID-IMMU1066>3.0.CO;2-#

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 168

  NiyonsabaFUshioHHaraMYokoiHTominagaMTakamoriKet alAntimicrobial peptides human beta-defensins and cathelicidin LL-37 induce the secretion of a pruritogenic cytokine IL-31 by human mast cells. J Immunol (2010) 184(7):3526–34.10.4049/jimmunol.0900712

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 169

  BefusADMowatCGilchristMHuJSolomonSBatemanA. Neutrophil defensins induce histamine secretion from mast cells: mechanisms of action. J Immunol (1999) 163(2):947–53.

  • Pubmed Abstract
  • Google Scholar

• 170

  SubramanianHGuptaKLeeDBayirAKAhnHAliH. Beta-defensins activate human mast cells via Mas-related gene X2. J Immunol (2013) 191(1):345–52.10.4049/jimmunol.1300023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 171

  PundirPCatalliALeggiadroCDouglasSEKulkaM. Pleurocidin, a novel antimicrobial peptide, induces human mast cell activation through the FPRL1 receptor. Mucosal Immunol (2014) 7(1):177–87.10.1038/mi.2013.37

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 172

  BehrendtHRosenkranzUSchmutzlerW. Ultrastructure of isolated human mast cells during histamine release induced by ionophore A 23187. Int Arch Allergy Appl Immunol (1978) 56(2):188–92.10.1159/000232022

  • CrossRef
  • Google Scholar

• 173

  BallettaALorenzDRummelAGerhardRBigalkeHWegnerF. Human mast cell line-1 (HMC-1) cells exhibit a membrane capacitance increase when dialysed with high free-Ca(2+) and GTPgammaS containing intracellular solution. Eur J Pharmacol (2013) 720(1-3):227–36.10.1016/j.ejphar.2013.10.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 174

  HosokawaJSuzukiKNakagomiDTamachiTTakatoriHSutoAet alRole of calcium ionophore A23187-induced activation of IkappaB kinase 2 in mast cells. Int Arch Allergy Immunol (2013) 161(Suppl 2):37–43.10.1159/000350357

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 175

  SheenCHSchleimerRPKulkaM. Codeine induces human mast cell chemokine and cytokine production: involvement of G-protein activation. Allergy (2007) 62(5):532–8.10.1111/j.1398-9995.2007.01345.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 176

  ShalitMRubinowAGranitLBar-SelaS. Codeine-induced mast cell degranulation in human skin: effect of calcium channel blockers. Ann Allergy (1987) 59(6):461–3.

  • Pubmed Abstract
  • Google Scholar

• 177

  KalesnikoffJHuberMLamVDamenJEZhangJSiraganianRPet alMonomeric IgE stimulates signaling pathways in mast cells that lead to cytokine production and cell survival. Immunity (2001) 14(6):801–11.10.1016/S1074-7613(01)00159-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 178

  PandeyVMiharaSFensome-GreenABolsoverSCockcroftS. Monomeric IgE stimulates NFAT translocation into the nucleus, a rise in cytosol Ca2+, degranulation, and membrane ruffling in the cultured rat basophilic leukemia-2H3 mast cell line. J Immunol (2004) 172(7):4048–58.10.4049/jimmunol.172.7.4048

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 179

  MatsudaKPiliponskyAMIikuraMNakaeSWangEWDuttaSMet alMonomeric IgE enhances human mast cell chemokine production: IL-4 augments and dexamethasone suppresses the response. J Allergy Clin Immunol (2005) 116(6):1357–63.10.1016/j.jaci.2005.08.042

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 180

  MarshallJSGomiKBlennerhassettMGBienenstockJ. Nerve growth factor modifies the expression of inflammatory cytokines by mast cells via a prostanoid-dependent mechanism. J Immunol (1999) 162(7):4271–6.

  • Pubmed Abstract
  • Google Scholar

• 181

  TomiokaMSteadRHNielsenLCoughlinMDBienenstockJ. Nerve growth factor enhances antigen and other secretagogue-induced histamine release from rat peritoneal mast cells in the absence of phosphatidylserine. J Allergy Clin Immunol (1988) 82(4):599–607.10.1016/0091-6749(88)90971-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 182

  YangZMarshallJS. Zymosan treatment of mouse mast cells enhances dectin-1 expression and induces dectin-1-dependent reactive oxygen species (ROS) generation. Immunobiology (2009) 214(4):321–30.10.1016/j.imbio.2008.09.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 183

  SundstromJBHairGAAnsariAASecorWEGilfillanAMMetcalfeDDet alIgE-FcepsilonRI interactions determine HIV coreceptor usage and susceptibility to infection during ontogeny of mast cells. J Immunol (2009) 182(10):6401–9.10.4049/jimmunol.0801481

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 184

  KulkaMAlexopoulouLFlavellRAMetcalfeDD. Activation of mast cells by double-stranded RNA: evidence for activation through Toll-like receptor 3. J Allergy Clin Immunol (2004) 114(1):174–82.10.1016/j.jaci.2004.03.049

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 185

  KingCAMarshallJSAlshurafaHAndersonR. Release of vasoactive cytokines by antibody-enhanced dengue virus infection of a human mast cell/basophil line. J Virol (2000) 74(15):7146–50.10.1128/JVI.74.15.7146-7150.2000

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 186

  McCurdyJDLinTJMarshallJS. Toll-like receptor 4-mediated activation of murine mast cells. J Leukoc Biol (2001) 70(6):977–84.10.1152/physrev.00031.2002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 187

  SmrzDBandaraGBeavenMAMetcalfeDDGilfillanAM. Prevention of F-actin assembly switches the response to SCF from chemotaxis to degranulation in human mast cells. Eur J Immunol (2013) 43(7):1873–82.10.1002/eji.201243214

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 188

  MacNeilAJJunkinsRDWuZLinTJ. Stem cell factor induces AP-1-dependent mast cell IL-6 production via MAPK kinase 3 activity. J Leukoc Biol (2014) 95(6):903–15.10.1189/jlb.0713401

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 189

  KojimaROhnoTIikuraMNikiTHirashimaMIwayaKet alGalectin-9 enhances cytokine secretion, but suppresses survival and degranulation, in human mast cell line. PLoS One (2014) 9(1):e86106.10.1371/journal.pone.0086106

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 190

  ErdeiAAndrasfalvyMPeterfyHTothGPechtI. Regulation of mast cell activation by complement-derived peptides. Immunol Lett (2004) 92(1-2):39–42.10.1016/j.imlet.2003.11.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 191

  HartmannKHenzBMKruger-KrasagakesSKohlJBurgerRGuhlSet alC3a and C5a stimulate chemotaxis of human mast cells. Blood (1997) 89(8):2863–70.

  • Pubmed Abstract
  • Google Scholar

• 192

  El-LatiSGDahindenCAChurchMK. Complement peptides C3a- and C5a-induced mediator release from dissociated human skin mast cells. J Invest Dermatol (1994) 102(5):803–6.10.1111/1523-1747.ep12378589

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 193

  MendesMAPalmaMS. Two new bradykinin-related peptides from the venom of the social wasp Protopolybia exigua (Saussure). Peptides (2006) 27(11):2632–9.10.1016/j.peptides.2006.05.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 194

  HochmanDJCollacoCRBrooksEG. Acrolein induction of oxidative stress and degranulation in mast cells. Environ Toxicol (2014) 29(8):908–15.10.1002/tox.21818

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 195

  PignattiPFrossiBPalaGNegriSOmanHPerfettiLet alOxidative activity of ammonium persulfate salt on mast cells and basophils: implication in hairdressers’ asthma. Int Arch Allergy Immunol (2013) 160(4):409–19.10.1159/000343020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 196

  SickEBrehinSAndrePCoupinGLandryYTakedaKet alAdvanced glycation end products (AGEs) activate mast cells. Br J Pharmacol (2010) 161(2):442–55.10.1111/j.1476-5381.2010.00905.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 197

  IddamalgodaALeQTItoKTanakaKKojimaHKidoH. Mast cell tryptase and photoaging: possible involvement in the degradation of extra cellular matrix and basement membrane proteins. Arch Dermatol Res (2008) 300(Suppl 1):S69–76.10.1007/s00403-007-0806-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 198

  CollacoCRHochmanDJGoldblumRMBrooksEG. Effect of sodium sulfite on mast cell degranulation and oxidant stress. Ann Allergy Asthma Immunol (2006) 96(4):550–6.10.1016/S1081-1206(10)63549-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 199

  YangWLeeSLeeJBaeYKimD. Silver nanoparticle-induced degranulation observed with quantitative phase microscopy. J Biomed Opt (2010) 15(4):045005.10.1117/1.3470104

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 200

  WangYChenZBaTPuJChenTSongYet alSusceptibility of young and adult rats to the oral toxicity of titanium dioxide nanoparticles. Small (2013) 9(9-10):1742–52.10.1002/smll.201201185

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 201

  SwindleEJColemanJWDeLeoFRMetcalfeDD. FcepsilonRI- and Fcgamma receptor-mediated production of reactive oxygen species by mast cells is lipoxygenase- and cyclooxygenase-dependent and NADPH oxidase-independent. J Immunol (2007) 179(10):7059–71.10.4049/jimmunol.179.10.7059

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 202

  WolfreysKOliveiraDB. Alterations in intracellular reactive oxygen species generation and redox potential modulate mast cell function. Eur J Immunol (1997) 27(1):297–306.10.1002/eji.1830270143

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 203

  KomiyamaHMiyakeKAsaiKMizunoKShimadaT. Cyclical mechanical stretch enhances degranulation and IL-4 secretion in RBL-2H3 mast cells. Cell Biochem Funct (2014) 32(1):70–6.10.1002/cbf.2973

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 204

  SouleBPBrownJMKushnir-SukhovNMSimoneNLMitchellJBMetcalfeDD. Effects of gamma radiation on FcepsilonRI and TLR-mediated mast cell activation. J Immunol (2007) 179(5):3276–86.10.4049/jimmunol.179.5.3276

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 205

  CabezaJMAcostaJAlesE. Mechanisms of granule membrane recapture following exocytosis in intact mast cells. J Biol Chem (2013) 288(28):20293–305.10.1074/jbc.M113.459065

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 206

  AnlaufMSchaferMKSchwarkTvon Wurmb-SchwarkNBrandVSiposBet alVesicular monoamine transporter 2 (VMAT2) expression in hematopoietic cells and in patients with systemic mastocytosis. J Histochem Cytochem (2006) 54(2):201–13.10.1369/jhc.5A6739.2005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 207

  Garcia-FaroldiGMeloFRBruemmerDConneelyOMPejlerGLundequistA. Nuclear receptor 4a3 (nr4a3) regulates murine mast cell responses and granule content. PLoS One (2014) 9(2):2.10.1371/journal.pone.0089311

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 208

  BorgesRDominguezNEstevez-HerreraJPeredaDMachadoJD. Vesicular Ca2+ mediates granule motion and exocytosis. Cell Calcium (2012) 51(3-4):338–41.10.1016/j.ceca.2011.12.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 209

  BonnemaisonMBackNLinYBonifacinoJSMainsREipperB. AP-1A controls secretory granule biogenesis and trafficking of membrane secretory granule proteins. Traffic (2014) 15(10):1099–121.10.1111/tra.12194

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 210

  BultemaJJDi PietroSM. Cell type-specific Rab32 and Rab38 cooperate with the ubiquitous lysosome biogenesis machinery to synthesize specialized lysosome-related organelles. Small GTPases (2013) 4(1):16–21.10.4161/sgtp.22349

  • Pubmed Abstract
  • CrossRef
  • Google Scholar