Abstract
Macrophages exhibit impaired phagocytosis, adhesion, migration, and cytokine production in space, hindering their ability to elicit immune responses. Considering that the combined effect of spaceflight microgravity and radiation is multiscale and multifactorial in nature, it is expected that contradictory findings are common in the field. This theory paper reanalyzes research on the macrophage spaceflight response across multiple timescales from seconds to weeks, and spatial scales from the molecular, intracellular, extracellular, to the physiological. Key findings include time-dependence of both pro-inflammatory activation and integrin expression. Here, we introduce the time-dependent, intracellular localization of MRTF-A as a hypothetical confounder of macrophage activation. We discuss the mechanosensitive MRTF-A/SRF pathway dependence on the actin cytoskeleton/nucleoskeleton, microtubules, membrane mechanoreceptors, hypoxia, oxidative stress, and intracellular/extracellular crosstalk. By adopting a multiscale perspective, this paper provides the first mechanistic answer for a three-decade-old question regarding impaired cytokine secretion in microgravity—and strengthens the connection between the recent advances in mechanobiology, microgravity, and the spaceflight immune response. Finally, we hypothesize MRTF involvement and complications in treating spaceflight-induced cardiovascular, skeletal, and immune disease.
1 Introduction
Macrophages (Mϕ) are an immune cell type featuring phenotypic flexibility in either fighting infection or promoting healing. Mϕ sense inflammation, activate upon sustained signaling, migrate to inflamed tissue, and secrete signaling cytokines. In spaceflight however, the unloading of weight in Mϕ has been known for at least 3 decades to dysregulate cytokine secretion (Chapes et al., 1992). The involvement of the cytoskeleton was first proposed then, but the underlying mechanism has been an open question since. In recent years, advances in mechanoimmunology have established that myocardin-related transcription factor-A (MRTF-A) is a cytoskeletal mechanosensor expressly involved in Mϕ pro-inflammatory activation and cytokine secretion (Yu et al., 2014). Thus, we aim to introduce MRTF in the context of spaceflight by taking a multiscale approach to past research on Mϕ dysregulation and other diseases.
1.1 Multiscale approaches
Multiscale approaches in mechanobiology consider molecules, single cells, tissues, and organs, including each of their varied responses across time scales, to resolve complex interactions between biology and mechanics (; ). Similarly complex, the combined environmental effect of spaceflight microgravity (apparent 10–4 × g) and radiation has been given a multiscale mechanobiology approach for cardiovascular disease () and muscle/bone loss (), but not for immune dysregulation. Yet current immune studies in microgravity vary in scale from drop-towers (seconds) to ballistic flights (minutes) to long-term spaceflight (months), reviewed in detail by , or microgravity is simulated for a few days in 3D random positioning machines (3D-RPM) and rotating wall vessel bioreactors (RWV), where constant rotation time-averages the gravity vector to be negligible ().
Mϕ are commonly given multifactorial analysis (; ) because their phenotype is affected by a dynamic balance of extracellular cytokine signaling, intracellular crosstalk, immune cell-cell interaction, and mechanical and physiological environment (; ). These factors are space- and time-dependent, and thus differential changes observed across experimental timescales were often interpreted as an adaptation to microgravity (; Paulsen et al., 2015; ). Instead of such broad interpretations, however, mechanistic understandings are necessary for safe, effective treatment of spaceflight diseases such as immune dysregulation (), cancer progression (), circadian rhythm disruption (Simmet et al., 2013), and accelerated atherosclerosis (). For example, blood-circulating monocytes are recruited as pro-inflammatory Mϕ toward atherosclerotic lesions because of many factors including radiation (Patel, 2020), reactive oxygen species (ROS) (Wang Y. et al., 2014), adhesion proteins (Yang et al., 2005), and motility ()—all of which are afflicted by spaceflight.
Here, we apply a multiscale analysis in reviewing literature and data comparatively across spatial and temporal perspectives on microgravity, mechanotransduction, radiation, and crosstalk. First, we briefly describe individual spaceflight effects in increasing order of space and time (Figure 1). Then, we propose mechanisms for the most well-studied Mϕ phenotype changes in space: pro/anti-inflammatory activation, morphology, migration, and phagocytosis. To address knowledge gaps, we introduce the role of emerin—a putative gravi-sensitive nuclear envelope protein (; Vahlensieck et al., 2022)—, novel microgravity mechanisms for arginase-1 (ARG1) regulation, and, most notably, a novel scale in the multiscale space milieu via the MRTF-A/SRF (serum response factor) pathway. Compared to live-cell imaging, transcriptomic analysis has traditionally been blind to the dynamic, intracellular localization of MRTF-A (; ). Furthermore, MRTF-A is currently not included in any KEGG database pathway, and its transcription program may be concealed by overarching pro-inflammatory signaling pathways. Mutations in MRTF cause severe immunodeficiency (Sprenkeler et al., 2021). Thus, introducing MRTF reinforces space studies that would otherwise have seemingly contradictory conclusions regarding suppression or activation of the pro-inflammatory (classical M1) response of the uniquely mechano-regulated Mϕ cell type.
FIGURE 1
1.2 MRTF-A transduces Mϕ pro-inflammatory signals
Mϕ pro-inflammatory activation and cytoskeletal reorganization occurs in a biphasic manner (; Ronzier et al., 2022): firstly in a chemical and secondly a mechanotransductive phase lasting 0–3 h and 3–24 h, respectively. In the first stage, activation of surface receptors induces NF-κB/p65 nuclear translocation. Secondly, actin polymerization modulates cytokine transcription/secretion via transport of MRTF-A to the nucleus where it slowly accumulates over 3 h and associates with serum response factor (SRF) or NF-κB/p65 transcription factors, or independently binds to SAP motifs of DNA (; ; Zhou et al., 2021). The mechanosensitivity of MRTF-A is well-studied; if mechanical force induces polymerization of globular (G)-actin to filamentous (F)-actin, then G-actin-bound MRTF-A is released and translocated to the nucleus (simplified “classical” model):
Figure 2 presents a simplified mechanistic overview of MRTF in Mϕ pro-inflammatory activation. Together with the comprehensive list of MRTF/SRF target genes by , inflammatory target genes include interleukin 6 (IL6), IL1Β, IL12B, and inducible nitric oxide synthase (INOS or NOS2) (; ; Yang et al., 2020). Other downstream effects include the secretion of pro-inflammatory cytokines IL-6, IL-12, and interestingly, tumor necrosis factor-α (TNF-α) ()—thus TNF-α secretion and TNF-α expression (p65 promoted) are regulated by specific mechanisms in Mϕ. This is supported with the understanding that Mϕ activation is metabolically regulated by epigenetic “brakes” (), and that MRTF physically interacts with NF-κB/p65 resulting in the mutual inhibition of them both () (Figure 2). Lastly, it is important to note that MRTF-A/SRF mediates actin and myosin gene expression (), thus facilitating “mechanoadaptation” (). We interpret this delayed feedback loop for cytoskeletal remodeling as a possible mechanism for long-term adaptation to microgravity.
FIGURE 2
Many studies, reviewed by Sun et al. (2021), have found the Mϕ NF-κB inflammatory pathway to be unaffected by microgravity. If not caused by NF-κB/p65, then what is the mechanism of Mϕ phenotypic change? The microgravity effect on the MRTF-A/SRF pathway has not been explored in Mϕ and has been rarely explored in other cell types. analyzed astronaut T-cell transcriptomic profiles, finding the majority of downregulated genes to be promoted by SRF. Later, in a similar spaceflight study by , it was found that microRNA-21 (miR-21) was downregulated. Relatedly, miR-21 is promoted by MRTF/SRF and is attributed to pro-inflammatory activation in Mϕ (Wang Z. et al., 2015; ). We emphasize the importance of research in Mϕ because they are implicated in diseases associated with spaceflight, such as atherosclerosis—where plaque-associated Mϕ overexpress MRTF-A ()—as well as circadian clock disruption (Shirato and Sato, 2022)—where Mϕ circadian clock components that regulate the timing of phagocytosis and motility are promoted by MRTF-A (; Xiong et al., 2021).
2 Multiscale analysis in approx. increasing order of space and time
2.1 Microgravity-induced mechanical unloading
Mechanical factors such as shear stress, extracellular matrix (ECM)/tissue stiffness, and spatial confinement () correlate to immune regimes that govern Mϕ phenotype throughout the body. Innate immune system function necessitates Mϕ motility and phagocytosis, both of which require rapid cytoskeletal remodeling (). Likewise, microgravity—which in drop towers and parabolic flights is studied in second-long intervals—induces rapid cytoskeletal restructuring via actin depolymerization, but Mϕ repolymerize actin and correct it within minutes (Thiel et al., 2019). We speculate that feedback loops associated with the cellular level of actin polymerization are involved. For example, MRTF can recruit protein complexes associated with chromatin remodeling (). The actin nucleoskeleton also regulates and remodels chromatin (Venit et al., 2021), and is similarly restructured in microgravity resulting in the modulation of mechano-sensitive genes ().
Furthermore, the Mϕ cytoskeleton is physically linked with the cytoplasmic membrane. This linkage mediates motility and phagocytosis (). Less studied in microgravity, there is evidence presented by that microgravity increases lipid membrane fluidity or decreases membrane tension. If this is true, then lipid rafts could be disrupted, for instance allowing free diffusion of caveolin-1 ()—a crucial protein for Mϕ phagocytosis (; Rubio et al., 2018). We mention that the quick response of the plasma membrane to mechanical forces may also play a role in the Mϕ oxidative burst reaction—which rapidly adapts to microgravity (; Thiel et al., 2017).
Membrane ion channels are also rapidly sensitive to membrane tension/fluidity and are known to have importance to inflammation, for instance inducing MRTF (Sharma et al., 2017). However, ion-channels are rarely studied in microgravity despite their mechanosensivity (). The two well-known mechano-sensitive Ca2+ ion-channels, transient receptor potential vanilloid 4 (TRPV4) and Piezo1, vary in activation responses to cytoskeletal structure, substrate stiffness/topology, and membrane tension/fluidity (Rahaman et al., 2014; ; ; Romero et al., 2019; Sun et al., 2019; ; ; Sianati et al., 2021). Another tension-sensitive ion channel, Hv1, is responsible for inducing superoxide production for the Mϕ oxidative burst reaction after phagocytosis (Ramsey et al., 2009). Interestingly, the channel has a mechanical history of up to 5 min (Pathak et al., 2016), which may have ramifications on microgravity platforms with cyclic loading e.g., 3D-RPM or RWV, or parabolic flight with a gravity period of ∼60 s.
2.2 Mechanotransduction
Gene expression is often studied on the timescale of hours in simulated microgravity bioreactors, which oscillate the gravity force usually between 10–15 rpm. Expression is not only induced by biochemical signaling, but also from the direct physical linkage of the cytoskeleton to the nucleoskeleton (). Remarkably, demonstrated nuclear stiffening under cyclic (0.14 Hz) mechanical force as small as 35 pN (near the weight of a Mϕ cell). They identified emerin, a ubiquitous nuclear lamin protein, to be involved independently from the nucleoskeleton. We identify emerin to be a potential confounding cause of nuclear stiffness discrepancies across simulated/spaceflight microgravity platforms—e.g., rotation frequency, substrate stiffness, or topology. Table 1 compares cell stiffness, migration, and filamentous actin (F-actin) levels across simulated microgravity platforms and culture methods that vary in substrate rigidity, adhesion, or extracellular matrix (ECM). Here, cells cultured on both rigid substrates and at 10–15 rpm (close to 0.14 Hz where emerin nuclear stiffening was observed) are more motile, stiffer, or exhibit greater actin polymerization (; ; Thompson et al., 2020; Wubshet et al., 2021), apparently contradicting general findings of spaceflight microgravity studies. It is worth noting that in normal gravity, cyclic tissue-stretching studies show significant MRTF translocation in fibroblasts at an optimum 0.1 Hz, but at relatively high levels of strain () compared to rotational simulated microgravity (1%–15% compared to almost 0%). Cytoskeletal strain may be negligible but emerin may not be. Emerin is known to be dependent on substrate-stiffness in modulating nuclear MRTF-A levels (Record et al., 2021).
TABLE 1
| Cell type | Platform | Culture method | Results | Study |
|---|---|---|---|---|
| J-111 monocyte | 3D-RPM, 60 rpm | Chamber slides (Lab-Tek) | ↓ F-actin | |
| ↓ Cell migration | ||||
| Human breast epithelial cell | 3D-RPM, 2 rpm | Cell culture flask (Fisher) | ↑ Nuclear volume | |
| MLO-Y4 Osteocyte | RWV, 15 rpm | Cell Rolling Tube (Thermo Scientific FormaTM) | ↑ Nuclear volume | Yang et al. (2018) |
| ↓ F-actin polymerization | ||||
| Human umbilical vein endothelial cells | 3D-RPM, ∼10 rpm | Petri Dish | ↓ Cell stiffness | |
| ↓ F-actin, microtubules | ||||
| Human osteoblast | 3D-RPM, ∼10 rpm | Adherent cell culture | ↓ Cell stiffness | Wubshet et al. (2021) |
| ↓ F-actin | ||||
| Rat bone marrow mesenchymal stem cell | RWV, 10 rpm | 2D cell culture slide | ↑ Cell stiffness | |
| ↑ F-actin polymerization | ||||
| Mouse mesenchymal stem cell | RWV, 15 rpm | SlideFlasks (2D plated cells) | ↓ Nuclear stiffness (not significant) | Thompson et al. (2020) |
| ↓ F-actin (not significant) |
Simulated microgravity alters nuclear and cytoskeletal structural dynamics in various cell types and culture methods. Boldened results indicate concordance with observed spaceflight microgravity motility studies. Although in the field of cell adhesion and migration, the generalized effect of cell mechanical characteristics is still unclear (). The nucleus is the stiffest organelle and contributes the most to cellular stiffness (Qi et al., 2016). Increased actin polymerization generally increases nuclear size and stiffness via nucleoskeletal remodeling (), thus reducing cellular motility (). Generally, cell motility is reduced in spaceflight and simulated microgravity across various cell types ().
After a few minutes in microgravity, microtubule arrangement is disrupted (Papaseit et al., 2000) and in the span of 5 days, microtubules are shorter and wavier in Mϕ (). Consequently, microtubule disruption induces the p38 mitogen-activated protein kinase (MAPK) pathway (); thus we hypothesize that microtubule disruption is the cause of p38 MAPK induction, and further upregulation of ARG1, that is observed in Mϕ in simulated and spaceflight microgravity (Wang C. et al., 2015; ). In fact, Mϕ ARG1 expression is induced by perturbing microtubules via chemical methods, yet is not affected by chromatin remodeling nor by ECM stiffness (). Alternatively, p38 MAPK induction is linked to mechanosensitive membrane proteins (). The timescale difference between membrane proteins and microtubule arrangement could factor in Mϕ arginine level variation observed between short- and long-term spaceflight (Thiel et al., 2021).
2.3 Intracellular localization and transport
Upon sustained LPS stimulation, MRTF-A/SRF cytoskeletal mechanotransduction from Mϕ activation is a slow process that takes up to 4 h vs. a few minutes for the early stage of NF-κB (). We hypothesize that delayed mechanotransduction causes experimentally observed “adaptations” to microgravity, and that inconsistencies observed across studies (Table 2) are time-dependent and pathway-specific. For example, cytokine expression/secretion of pro-inflammatory IL-6/IL-12/IL-1β is significantly downregulated after 4–24 h, concordant with our theory that actin disruption in microgravity inhibits the MRTF-A/SRF pathway. Interestingly, if normal gravity is restored post-48 h, then cytokine expression/secretion appears to recover (Table 2). Likewise, there is no time dependence of NF-κB-dependent TNF-α expression/secretion as it is consistently downregulated in both simulated and spaceflight microgravity. We also consider an alternative mechanotransductive pathway, p38 MAPK, in two studies where the data are available (Table 2), which may explain inconsistency in Table 2 regarding IL-6 and IL-12 expression/secretion, because p38 MAPK activation results in increased IL-6 and decreased IL-12b expression (Wang C. et al., 2015).
TABLE 2
| Cell type | Platform | Culture method | Time after stimulation | Results | Study |
|---|---|---|---|---|---|
| U937 differentiated to Mϕ after RWV | RWV, 18 rpm | 10-ml RCCS-D bulk vessels (Synthecon) | 1, 2, 3 h after 12 h differentiation and 72 h RWV | ↓ IL-6 secretion, expression, exacerbated over time | Wang et al. (2020) |
| ↓ TNF-α secretion, exacerbated over time | |||||
| ↓ TNF-α expression | |||||
| ↓ p38 MAPK pathway | |||||
| RAW 264.7 & primary mouse Mϕ | RWV, unspecified rpm | Adherent microcarrier beads | 4 h after 24 h RWV | IL-1β expression (ns) | Wang C. et al. (2014) |
| ↓ TNF-α expression | |||||
| Unchanged MAPK pathway | |||||
| Primary mouse Mϕ | RWV, 12–25 rpm | Adherent microcarrier beads | 4 h after 24 h RWV | ↑ IL-6 expression and concentration | Wang C. et al. (2015) |
| ↓ IL-12 subunit B expression | |||||
| ↑ p38 MAPK pathway | |||||
| 24 h after 24 h RWV | ↓ (less significant) IL-12 subunit B concentration | ||||
| ↑ p38 MAPK pathway | |||||
| ↓ TNF-α expression | |||||
| RAW 264.7 murine Mϕ | RWV, 14 rpm | 10-ml RCCS-D bulk vessels (Synthecon) | 48 h after 48 h RWV | ↓ IL-6, IL-12 secretion | |
| ↓ TNF-α, NO secretion | |||||
| Human blood monocyte stimulated with LPS | Spaceflight | In vivo, then whole blood cultured, and stimulated | under 1 g 48h, after ∼350 h spaceflight | ↓ IL-6 expression | |
| ↑ IL-1β expression | |||||
| ↓ TNF-α expression | |||||
| ↓ IL-10 expression | |||||
| Mouse splenocyte stimulated with LPS | Spaceflight | In vivo, then flat-bottom plated, and stimulated | under 1 g 48h, after ∼312 h spaceflight | ↑ IL-6 secretion | |
| IL-12 (ns) | |||||
| ↓ TNF-α secretion | |||||
| ↑ IL-10 secretion | |||||
| RAW 264.7 murine Mϕ | RWV, 14 rpm | Adherent microcarrier beads | 72 h RWV after 48 h of stimulation | IL-6 (ns) | |
| ↑ IL-12 secretion | |||||
| ↓ TNF-α secretion | |||||
| ↑ IL-10 secretion |
After Mϕ stimulation, cytokine responses are altered under microgravity over time. Boldened results indicate a reduction in pro-inflammatory cytokines TNF-α/IL-6/IL-12/IL-1β, and thus concordance with our theory of microgravity-based MRTF inhibition. Anti-inflammatory cytokines include IL-10. Protocols between studies varied the order between pro-inflammatory stimulation and microgravity.
Our identification of MRTF-A/SRF pathway inhibition is the first time that altered Mϕ cytokine profiles have been linked to microgravity. Not only cytokines, but also a previous experiment () (Table 2) showed reduced nitric oxide (NO) secretion. In correlation, MRTF-A/SRF promotes iNOS (Yang et al., 2020) which is essential for killing pathogens after phagocytosis. We also conjecture that MRTF-A is a factor in impaired Mϕ phagocytosis in microgravity. MRTF-A-promoted genes involved in phagocytosis include caveolin-1 (CAV1) () and intercellular adhesion molecule-1 (ICAM-1) (Zhong et al., 2021; ). Unfortunately, ICAM-1 regulation by MRTF-A is not consistent across cell type and is unclear in Mϕ, and it may also be NF-κB-dependent (; ). Additionally, the effect of microgravity on ICAM-1 regulation is controversial, varying between cell types (Paulsen et al., 2014; Tauber et al., 2017; ). For Mϕ, it is apparently time-dependent (Table 3), but no microgravity-linking mechanism has been identified yet.
TABLE 3
| Cell type | Platform | Culture method | Time | Results | Study |
|---|---|---|---|---|---|
| Non-differentiated Monocytes, both stimulated and non-stimulated during flight | |||||
| U937 human monocyte | Parabolic flight | Nutrimix bag (B. Braun Melsungen) | 20 s | No change in ICAM-1 surface expression | Paulsen et al. (2015) |
| U937 human monocyte | Sub-orbital rocket | Plastic Syringe | 6 min | No change in ICAM-1 mRNA levels | Paulsen et al. (2015) |
| Differentiated Monocytes/Mϕ | |||||
| U937 human Mϕ-like monocyte | Parabolic flight | Nutrimix bag (B. Braun Melsungen) | 20 s | ↑ Slight ICAM-1 surface expression | Paulsen et al. (2015) |
| Human primary Mϕ and U937 human Mϕ-like monocyte | RWV, 60 rpm | Serological pipette | 24–120 h | ↑ Surface ICAM-1 trending down (not significant) over time | Paulsen et al. (2015) |
| U937 human Mϕ-like monocyte | Geocentric orbit | Polycarbonate slide | 120 h | ↑ Surface ICAM-1 | Paulsen et al. (2014) |
| Severe disturbance of the cytoskeleton | |||||
| Primary human Mϕ | Low-earth orbit | Polycarbonate slide | 264 h | ↓ Surface ICAM-1 | Tauber et al. (2017) |
| No disturbance of the cytoskeleton | |||||
| 720 h | ↓↓ Surface ICAM-1 | ||||
| Altered cytoskeletal architecture | |||||
ICAM-1 surface expression over time in differentiated and non-differentiated Mϕ/monocytes. Simulated and spaceflight microgravity modulated U937 and human Mϕ ICAM-1 surface levels, but did not affect non-differentiated monocytes, even transcriptionally. Note, a microgravity phase of parabolic flight lasts 20 s, not enough time for differential transcription, thus differential surface expression of ICAM-1 may be attributed to membrane/cytoskeletal dynamics or other post-translational regulatory factors.
ICAM-1 is a transmembrane protein found clustered in lipid rafts (Tilghman and Hoover, 2002) and anchored to the actin cytoskeleton (Schaefer et al., 2014). Induction of Mϕ ICAM-1 levels off after ∼12 h (according to Zhong et al. (2021) with 0, 12, and 24 h time points). Therefore, we postulate that MRTF-A is a delayed regulator of ICAM-1 expression in Mϕ. In a similar mechanism, found that in vascular endothelial cells, nuclear MRTF-A binds to NF-κB/p65, inhibiting p65 promotion of ICAM-1. The involvement of both NF-κB and MRTF-A/SRF pro-inflammatory pathways may explain the inconsistency across cell types about ICAM-1 expression in microgravity. For example in Table 3, we compare Mϕ to non-differentiated monocytes, a cell type that exhibits unchanged ICAM-1 levels during microgravity flights. Correspondingly, microarray analysis of these monocytes has shown that only two pathways are weakly altered after 6 min of pro-inflammatory stimulation: NF-κB, and the Epstein-Barr virus infection (Paulsen et al., 2015), which is related to the nuclear transport and function of p65 (). These two pathways correlate with the first phase of pro-inflammatory activation. Comparatively in Mϕ and pre-differentiated monocytes, relative surface ICAM-1 levels trended downwards with time (Table 3). We interpret this as either as a resurgence of MRTF-A as the actin cytoskeleton recovers after 24 h or as a separate, unknown mechanism for ICAM-1 downregulation in the long term. For example, microRNA-21 is downregulated in T-cells under microgravity (). miR-21 is MRTF/SRF promoted, and attributed to “mechanical memory” of at least 20 days in bone mesenchymal stem cell (BMSC) fibrogenesis (Wang Z. et al., 2015; ). Relatedly in Mϕ, miR-21 increases expression of ICAM-1 ().
2.4 Hydromechanics of simulated and spaceflight microgravity
Altered hydromechanics: fluid shear against the walls of rotational culture vessels, gravitational buoyancy, buoyant mixing, and altered chemical/gas diffusion are commonly assumed to be negligible in simulated and spaceflight microgravity but are still part of the multiscale space milieu (Poon, 2020; ). For instance, Mϕ ROS production is quickly responsive to shear forces, which are observed in RPM bioreactors that rotate randomly (). Moreover, hydromechanical transport is a factor of altered phenotype of Mϕ when they are cultured on 2D vs. 3D substrate (). Therefore, some microgravity hydrodynamic environments may exhibit altered chemical/gas diffusion, conferring local Mϕ hypoxia in culture. Overall effects may include activation of the p38 MAPK pathway (; )—a pathway that exhibits contradictory activation or suppression in simulated microgravity (Table 2). Another potential effect is altered metabolism, as glycolytic lactic acid accumulation in culture may stimulate pro-inflammatory cytokine expression in Mϕ (Shi et al., 2021). Whether the microgravity altering effect on Mϕ metabolism can be attributed to both mechanical factors and hypoxic state remains to be elucidated.
Based on the paucity of evidence linking hypoxia with mechanotransduction, it is most likely there is only indirect interaction between the two. Independent of hypoxia, inflammatory cytokines such as IL-6, IL-18, and TNF-α induce hypoxia-inducible factors (HIF) in Mϕ (Vogel et al., 2019). HIF-1α is well studied in microgravity: cultured Mϕ on adherent microbeads in RWV and observed no significant change of HIF-1α expression in Mϕ, yet observed upregulation of vascular endothelial growth factor (VEGF) secretion and downregulation of TNF-α. It is unclear whether this finding is caused by hypoxia, ROS, or mechanotransductive pathways. For example, the ERK/MAPK signaling pathway induces VEGF secretion across many cell types (; ). Interestingly, myofibroblast differentiation is suppressed in hypoxia due to HIF-1α dependent inhibition of RhoA, a key remodeler of the actin cytoskeleton, overall hindering the MRTF/SRF pathway (). Furthermore, hypoxia upregulates Mϕ expression of ICAM-1 likely in a p53 or NF-κB dependent manner (). Generally, hypoxia polarizes Mϕ toward anti-inflammatory phenotypes (). Thus, we hypothesize that hypoxia and microgravity act independently to suppress Mϕ pro-inflammatory phenotype.
2.5 Radiation and oxidative stress
The timespan of space radiation study ranges from weeks to months vs. microgravity study timespans of minutes to days. In contrast to hypoxia, we hypothesize that low-dose space radiation counteracts the effect of microgravity on Mϕ immune function. The immunomodulatory effect of radiation is dosage-dependent and depends on a multitude of factors including DNA damage, ROS generation, and modulation of inflammation pathways. A review in a cancer radiotherapy context by Wu et al. (2017) acknowledges that low-dosage radiation (comparable to spaceflight-relevant dosage) generally induces anti-inflammatory (alternative M2) activation—possibly by inactivation of p38 MAPK—but high doses induce pro-inflammatory (classical M1) activation, possibly by activation of p53—a well-studied transcription factor that stimulates DNA repair or apoptosis. Alternatively, p53 is transported by dynein on microtubules (), similar to p38 MAPK (see Section 2.2Mechanotransduction).
The abrogation of Mϕ phenotypic disorder observed in space may be misattributed to adaptation to microgravity instead of the long-term effects of radiation. For instance, we hypothesize the apparent reversal of ARG1 (Thiel et al., 2021) and surface ICAM-1 expression between 11–30 days in orbital spaceflight (Table 3) to be caused by inactivation of either p38 MAPK or downregulation of miR-21 (see Section 2.3). A competing mechanism may be membrane-based: oxidative stress is caused by DNA damage and other radiation mechanisms e.g., upregulation of NADPH oxidase (NOX) causes ROS production (Sakai et al., 2018). ROS-based lipid peroxidation causes membrane fluidity reduction ()—opposite to the effect of microgravity on fluidity (see Section 2.1). Nonetheless, there is evidence that space radiation alone is not significant for ROS production, but requires microgravity as a “synergistic potentiator” (Smith et al., 2012; Ran et al., 2016; ). Considering the synergism between microgravity and radiation, it is possible that they involve MRTF-A and p65 (NF-κB), respectively; both transcription factors form a complex to promote iNOS () and ROS-producing NOX4 (). Relatedly in vascular endothelial cells, oxidized low-density lipoprotein (oxLDL) causes cellular acetylation of MRTF-A promoting nuclear translocation and modulation of ICAM-1 expression (). Therefore, chronic ROS generation could be another mechanism for the apparent reversal of ICAM-1 surface expression in spaceflight.
2.6 Intercellular and physiological crosstalk
Mϕ dysregulation translates to impaired interaction with other immune cells. For example, T lymphocyte interaction is essential for antigen presentation, but may be slowed by Mϕ migration impairment in microgravity (). Additionally, Mϕ reduced surface ICAM-1 expression in spaceflight (Table 3) may hinder their adhesion and subsequent activation of CD4+ T lymphocytes (). Not only considering immune cells, observed the reduction of anti-inflammatory bacteria cultured under simulated microgravity. Wang et al. (2020) found live mouse hindlimb unloading (that is, a simulation of weightlessness by suspending hindlimbs in the air) to cause mouse gut microbiota dysbiosis and suppression of the p38 and ERK/MAPK pathways in intestinal Mϕ. Here, p38 and ERK was rescued by probiotics, thus microgravity may mechanically regulate the microbiota-immune axis. Zooming-out to the tissue scale, altered tensional homeostasis (such as that caused by microgravity mechanical unloading) impairs the transport of MRTF to the nucleus (). Lastly, Mϕ are mediators of intercellular signals. As observed in coculture by , radiation-induced apoptosis signaling is propagated by Mϕ, potentially increasing tissue damage. Damaged-cell intercellular signaling is enough to stimulate Mϕ differentiation/activation, regardless of Mϕ irradiation state.
Monocyte/Mϕ differentiation also depends on both microgravity and radiation. Shi et al. (2021) observed that microgravity suppresses differentiation of Mϕ to either pro-inflammatory or anti-inflammatory phenotype; yet, Coates et al. (2008) observed that radiation augments Mϕ differentiation. Earlier (Section 2.5), we have hypothesized that—regarding the innate immune response—radiation counteracts microgravity. But regarding bone degeneration, the effect of microgravity and radiation appears additive by increased fusion of monocyte/Mϕ in forming multinucleated osteoclasts (; Shanmugarajan et al., 2017). Osteal Mϕ also communicate locally with other cells: osteopontin, a versatile protein involved in bone cell migration, is promoted in osteoblasts under microgravity (Smith, 2020). Osteopontin also acts as a cytokine for Mϕ () generally promoting phagocytic activity (Schuch et al., 2016). Mϕ produces osteopontin when stimulated with anti-inflammatory IL-18 and IL-10 (), both of which are regulated by oxidative and mechanical stress. Thus, the effect of altered physical environments on Mϕ differentiation/activation may consequently dysregulate Mϕ chemical signaling to other tissues.
3 Conclusion and recommendations
In summary, we have discussed the hypothetical multiscale involvement of the MRTF-A/SRF pathway in the dysregulation of Mϕ under microgravity and radiation. MRTF-A is a regulator and adaptor of cytoskeletal architecture, migration, phagocytosis, ROS generation, cytokine secretion/expression, and adherence proteins. Thus, its involvement is a probable answer to the question of Mϕ phenotypic change in microgravity. However, MRTF-A/SRF has many complications; its function is dependent on cell type and is not completely understood in Mϕ (). MRTF-A is post-translationally acetylated, phosphorylated, or SUMOylated by many factors, including intracellular crosstalk with other mechanotransductive pathways such as ERK (), YAP/TAZ (), and p38 MAPK in Mϕ (Ronkina et al., 2016), that alter its cellular localization. Crosstalk with MRTF is also bidirectional (Speight et al., 2016), so we suggest that MRTF is a culprit in impaired nuclear translocation of TAZ under simulated microgravity—as observed by to occur in BMSC in a noncanonical, F-actin-dependent manner. Furthermore, the nuclear transport of MRTF depends on nuclear lamina-associated proteins as well as cytoskeletal/nucleoskeletal architecture (; Sidorenko et al., 2022). Related mechanical factors such as shear stress, vibration, and oscillation in simulated microgravity bioreactors may influence MRTF translocation. Not only mechanical but also chemical factors, such as hypoxia and oxidative stress, induce the MRTF/SRF pathway in Mϕ (Yang et al., 2020). Therefore, we recommend that future studies attempt to pinpoint MRTF-A/SRF modulation to one of these factors, not excluding microgravity.
We have primarily discussed the connection of MRTF-A to the actin cytoskeleton. However, we also recommend further study in microtubule disruption that may alter the p38 MAPK pathways. p38 MAPK is known to mediate MRTF-A phosphorylation, the consequence of which was found recently by Zhang M. et al. (2021) to be activation of the MRTF-A/p65 complex to promote IL-6 in Mϕ. Furthermore, the consequence of radiation damage on microtubules is rarely studied although may be negligible (Zaremba and Irwin, 1981; Bruni et al., 2020). It is possible that radiation alters the transport of p38 MAPK and p65 NF-κB on microtubules. Thus, the two separate effects may modulate different pathways: NF-κB may depend on radiation and MRTF/SRF may depend on microgravity. To test this, we first recommend co-quantification of the MRTF-A vs. p65 NF-κB nuclear/cytoplasmic ratio, compared with the F/G actin ratio, under simulated microgravity followed by such in simulated radiation.
Mϕ are one of the most radioresistant and redox-resistant cell types, important for their role in the clearance of radiation-damaged, apoptotic cells (). However, Mϕ are mechano-sensitive and uniquely mechano-regulated (Sullivan et al., 2011) as described previously (Section 1.1). Importantly, the dominant effects of microgravity vs. radiation depend on cell type, thus directed treatment of spaceflight diseases should be specific to cell type. For example, spaceflight acceleration of atherosclerosis could be treated by activating p53, as it plays a crucial role in preventing the disease (). However, p53 in Mϕ potentiates anti-inflammation and is already upregulated in microgravity (Shi et al., 2021), thus by activating p53 we may inadvertently expedite spaceflight immune dysregulation.
MRTF-A is widely expressed across many cell types and is implicated in cardiovascular, musculoskeletal, and immune diseases () relevant to spaceflight. For instance, MRTF-A is upregulated in blood-circulating Mϕ associated with atherosclerotic lesions, thus a drug that supplants MRTF-A (Velasquez et al., 2013; Yu-Wai-Man et al., 2017) may inadvertently accelerate atherosclerosis in space. Similar conclusions can be made with spaceflight diseases such as non-alcoholic fatty liver disease (), related to MRTF (Zhang L. et al., 2021). Currently, no safe drugs have been proven for the treatment of space-induced cardiovascular disease, and evaluations of potential drugs is often contradictory (). In conclusion, future investigation of treatment for spaceflight diseases can be improved by a multiscale mechanobiological understanding of the consequence of microgravity × radiation environments on Mϕ. Our work contributes to this understanding by introducing MRTF.
Statements
Author contributions
The author confirms being the sole contributor of this work and has approved it for publication.
Funding
Open access publication fees of this work are supported by the Cornell Open Access Publication Fund.
Acknowledgments
The author thanks Virginia Katherine Blackwell, Bijan Harandi, Alicia C. Gibbons, Olivia Siu, Amy Rees, Nadjet Cornejal, Iris Irby, Kristina Sattler, Tao Sheng, Nicholas Syracuse, Drs. Sigrid S. Reinsch, Hami E. Ray, David Loftus, Sergio R. Santa Maria, Egle Cekanaviciute, Amber M. Paul, and Jessica A. Lee for supporting the NASA Space Life Sciences Training Program (SLSTP) and for helpful discussions that inspired this paper.
Conflict of interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
AdrianA.SchoppmannK.SromickiJ.BrungsS.von der WiescheM.HockB.et al (2013). The oxidative burst reaction in mammalian cells depends on gravity. Cell. Commun. Signal.11 (1), 98. 10.1186/1478-811X-11-98
2
AnJ.NagaishiT.WatabeT.NaruseT. K.WatanabeM.KimuraA. (2017). MKL1 expressed in macrophages contributes to the development of murine colitis. Sci. Rep.7 (1), 13650. 10.1038/s41598-017-13629-0
3
AnJ.NaruseT. K.HinoharaK.SoejimaY.SawabeM.NakagawaY.et al (2019). MRTF-A regulates proliferation and survival properties of pro-atherogenic macrophages. J. Mol. Cell. Cardiol.133, 26–35. 10.1016/j.yjmcc.2019.05.015
4
AnR.LeeJ. A. (2022). Camdles: CFD-DEM simulation of microbial communities in spaceflight and artificial microgravity. Life12 (5), 660. 10.3390/life12050660
5
AventaggiatoM.BarrecaF.VernucciE.BizzarriM.FerrettiE.RussoM. A.et al (2020). Putative receptors for gravity sensing in mammalian cells: The effects of microgravity. Appl. Sci.10 (6), 2028. 10.3390/app10062028
6
BagaevA. V.GaraevaA. Y.LebedevaE. S.PichuginA. V.AtaullakhanovR. I.AtaullakhanovF. I. (2019). Elevated pre-activation basal level of nuclear NF-κB in native macrophages accelerates LPS-induced translocation of cytosolic NF-κB into the cell nucleus. Sci. Rep.9, 4563. 10.1038/s41598-018-36052-5
7
BaqaiF. P.GridleyD. S.SlaterJ. M.Luo-OwenX.StodieckL. S.FergusonV.et al (2009). Effects of spaceflight on innate immune function and antioxidant gene expression. J. Appl. Physiol.106 (6), 1935–1942. 10.1152/japplphysiol.91361.2008
8
BasirunC.FerlazzoM. L.HowellN. R.LiuG.-J.MiddletonR. J.MartinacB.et al (2021). Microgravity × radiation: A space mechanobiology approach toward cardiovascular function and disease. Front. Cell. Dev. Biol.9, 750775. 10.3389/fcell.2021.750775
9
BeheshtiA.ChakravartyK.FogleH.FazeliniaH.SilveiraW. A. d.BoykoV.et al (2019). Multi-omics analysis of multiple missions to space reveal a theme of lipid dysregulation in mouse liver. Sci. Rep.9 (1), 19195. 10.1038/s41598-019-55869-2
10
BhattacharyaS.CalarK.de la PuenteP. (2020). Mimicking tumor hypoxia and tumor-immune interactions employing three-dimensional in vitro models. J. Exp. Clin. Cancer Res.39 (1), 75. 10.1186/s13046-020-01583-1
11
BianH.LiF.WangW.ZhaoQ.GaoS.MaJ.et al (2017). MAPK/p38 regulation of cytoskeleton rearrangement accelerates induction of macrophage activation by TLR4, but not TLR3. Int. J. Mol. Med.40 (5), 1495–1503. 10.3892/ijmm.2017.3143
12
BloomfieldS. A.MartinezD. A.BoudreauxR. D.MantriA. V. (2016). “Microgravity stress: Bone and connective tissue,” in Comprehensive physiology (John Wiley & Sons), 645–686. 10.1002/cphy.c130027
13
Botello-SmithW. M.JiangW.ZhangH.OzkanA. D.LinY.-C.PhamC. N.et al (2019). A mechanism for the activation of the mechanosensitive Piezo1 channel by the small molecule Yoda1. Nat. Commun.10 (1), 4503. 10.1038/s41467-019-12501-1
14
BrungsS.HauslageJ.HemmersbachR. (2019). Validation of random positioning versus clinorotation using a macrophage model system. Microgravity Sci. Technol.31 (2), 223–230. 10.1007/s12217-019-9687-0
15
BruniL.ManghiM.GioscioE.CaorsiV.RizziF. M.CrociS. (2020). Ionizing radiation effects on Hs578Bst microtubules. Front. Phys.8, 465. 10.3389/fphy.2020.579081
16
BryantS. L.ShresthaN.OxfordJ.CornellK.FologeaD. (2017). Simulated microgravity conditions modulate Ca2+ transport through TRPV4 channels. Biophysical J.112 (3), 251a. 10.1016/j.bpj.2016.11.1371
17
BuravkovaL. B.RudimovE. G.AndreevaE. R.GrigorievA. I. (2018). The ICAM-1 expression level determines the susceptibility of human endothelial cells to simulated microgravity. J. Cell. Biochem.119 (3), 2875–2885. 10.1002/jcb.26465
18
CessC. G.FinleyS. D. (2020). Multi-scale modeling of macrophage-T cell interactions within the tumor microenvironment. PLoS Comput. Biol.16 (12), e1008519. 10.1371/journal.pcbi.1008519
19
ChangT. T.WaltherI.LiC.-F.BoonyaratanakornkitJ.GalleriG.MeloniM. A.et al (2012). The Rel/NF-κB pathway and transcription of immediate early genes in T cell activation are inhibited by microgravity. J. Leukoc. Biol.92 (6), 1133–1145. 10.1189/jlb.0312157
20
ChenZ.LuoQ.LinC.KuangD.SongG. (2016). Simulated microgravity inhibits osteogenic differentiation of mesenchymal stem cells via depolymerizing F-actin to impede TAZ nuclear translocation. Sci. Rep.6 (1), 30322. 10.1038/srep30322
21
ChapesS. K.MorrisonD. R.GuikemaJ. A.LewisM. L.SpoonerB. S. (1992). Cytokine secretion by immune cells in space. J. Leukoc. Biol.52 (1), 104–110. 10.1002/jlb.52.1.104
22
CoatesP. J.RundleJ. K.LorimoreS. A.WrightE. G. (2008). Indirect Macrophage Responses to Ionizing Radiation: Implications for Genotype-Dependent Bystander Signaling. Cancer Res.68 (2), 450–456. 10.1158/0008-5472.CAN-07-3050
23
CrucianB. E.ChoukèrA.SimpsonR. J.MehtaS.MarshallG.SmithS. M.et al (2018). Immune system dysregulation during spaceflight: Potential countermeasures for deep space exploration missions. Front. Immunol.9, 1437. 10.3389/fimmu.2018.01437
24
CrucianB.StoweR.QuiriarteH.PiersonD.SamsC. (2011). Monocyte phenotype and cytokine production profiles are dysregulated by short-duration spaceflight. Aviat. Space Environ. Med.82 (9), 857–862. 10.3357/asem.3047.2011
25
CuendaA.RousseauS. (2007). p38 MAP-Kinases pathway regulation, function and role in human diseases. Biochim. Biophys. Acta1773 (8), 1358–1375. 10.1016/j.bbamcr.2007.03.010
26
CuiY.HameedF. M.YangB.LeeK.PanC. Q.ParkS.et al (2015). Cyclic stretching of soft substrates induces spreading and growth. Nat. Commun.6 (1), 6333. 10.1038/ncomms7333
27
de la HabaC.PalacioJ. R.MartínezP.MorrosA. (2013). Effect of oxidative stress on plasma membrane fluidity of THP-1 induced macrophages. Biochim. Biophys. Acta1828 (2), 357–364. 10.1016/j.bbamem.2012.08.013
28
DecanoJ. L.AikawaM. (2018). Dynamic macrophages: Understanding mechanisms of activation as guide to therapy for atherosclerotic vascular disease. Front. Cardiovasc. Med.5, 97. 10.3389/fcvm.2018.00097
29
DeymierA. C.SchwartzA. G.LimC.WingenderB.KotiyaA.ShenH.et al (2020). Multiscale effects of spaceflight on murine tendon and bone. Bone131, 115152. 10.1016/j.bone.2019.115152
30
DupontS.WickströmS. A. (2022). Mechanical regulation of chromatin and transcription. Nat. Rev. Genet., 1–20. 10.1038/s41576-022-00493-6
31
ElGindiM.SapudomJ.IbrahimI. H.Al-SayeghM.ChenW.Garcia-SabatéA.et al (2021). May the force Be with you (or not): The immune system under microgravity. Cells10 (8), 1941. 10.3390/cells10081941
32
EsnaultC.StewartA.GualdriniF.EastP.HorswellS.MatthewsN.et al (2014). Rho-actin signaling to the MRTF coactivators dominates the immediate transcriptional response to serum in fibroblasts. Genes. Dev.28 (9), 943–958. 10.1101/gad.239327.114
33
FangF.YangY.YuanZ.GaoY.ZhouJ.ChenQ.et al (2011). Myocardin-related transcription factor A mediates OxLDL-induced endothelial injury. Circ. Res.108 (7), 797–807. 10.1161/CIRCRESAHA.111.240655
34
FantuzziG. (Editor) (2003). Cytokine knockouts (Totowa, NJ: Humana Press). 10.1007/978-1-59259-405-4
35
Finch-EdmondsonM.SudolM. (2016). Framework to function: Mechanosensitive regulators of gene transcription. Cell. Mol. Biol. Lett.21 (1), 28. 10.1186/s11658-016-0028-7
36
FritzscheM. (2020). Thinking multi-scale to advance mechanobiology. Commun. Biol.3 (1), 469. 10.1038/s42003-020-01197-5
37
FuJ.ZhuL.TuW.WangX.PanY.BaiY.et al (2019). Macrophage-Mediated bystander effects after different irradiations through a p53-dependent pathway. Radiat. Res.193 (2), 119–129. 10.1667/RR15354.1
38
GauD.RoyP. (2018). SRF’ing and SAP’ing – The role of MRTF proteins in cell migration. J. Cell. Sci.131 (19), jcs218222. 10.1242/jcs.218222
39
GiannakakouP.SackettD. L.WardY.WebsterK. R.BlagosklonnyM. V.FojoT. (2000). p53 is associated with cellular microtubules and is transported to the nucleus by dynein. Nat. Cell. Biol.2 (10), 709–717. 10.1038/35036335
40
GomesT.SongY.BredeD. A.XieL.GutzkowK. B.SalbuB.et al (2018). Gamma radiation induces dose-dependent oxidative stress and transcriptional alterations in the freshwater crustacean Daphnia magna. Sci. Total Environ.628–629, 206–216. 10.1016/j.scitotenv.2018.02.039
41
GorgoulisV. G.ZacharatosP.KotsinasA.KletsasD.MariatosG.ZoumpourlisV.et al (2003). p53 activates ICAM-1 (CD54) expression in an NF-kappaB-independent manner. EMBO J.22 (7), 1567–1578. 10.1093/emboj/cdg157
42
GuentherC.FaisalI.UotilaL. M.AsensM. L.HarjunpääH.SavinkoT.et al (2019). A β2-integrin/MRTF-A/SRF pathway regulates dendritic cell gene expression, adhesion, and traction force generation. Front. Immunol.10, 1138. 10.3389/fimmu.2019.01138
43
GuilluyC.OsborneL. D.Van LandeghemL.SharekL.SuperfineR.Garcia-MataR.et al (2014). Isolated nuclei adapt to force and reveal a mechanotransduction pathway in the nucleus. Nat. Cell. Biol.16 (4), 376–381. 10.1038/ncb2927
44
GuoY.-J.PanW.-W.LiuS.-B.ShenZ.-F.XuY.HuL.-L. (2020). ERK/MAPK signalling pathway and tumorigenesis. Exp. Ther. Med.19 (3), 1997–2007. 10.3892/etm.2020.8454
45
HammondT. G.HammondJ. M. (2001). Optimized suspension culture: The rotating-wall vessel. Am. J. Physiol. Ren. Physiol.281 (1), F12–F25. 10.1152/ajprenal.2001.281.1.F12
46
HanY.ShaoD.HanC.HuangQ.ZhaoW. (2022). Response of human gut microbiota under simulated microgravity. Appl. Microbiol. Biotechnol.106 (13-16), 5221–5231. 10.1007/s00253-022-12045-3
47
HayashiK.MuraiT.OikawaH.MasudaT.KimuraK.MuehlichS.et al (2015). A novel inhibitory mechanism of MRTF-A/B on the ICAM-1 gene expression in vascular endothelial cells. Sci. Rep.5 (1), 10627. 10.1038/srep10627
48
HippL.BeerJ.KuchlerO.ReisserM.SinskeD.MichaelisJ.et al (2019). Single-molecule imaging of the transcription factor SRF reveals prolonged chromatin-binding kinetics upon cell stimulation. Proc. Natl. Acad. Sci. U. S. A.116 (3), 880–889. 10.1073/pnas.1812734116
49
HoC. Y.JaaloukD. E.VartiainenM. K.LammerdingJ. (2013). Lamin A/C and emerin regulate MKL1–SRF activity by modulating actin dynamics. Nature497 (7450), 507–511. 10.1038/nature12105
50
HoffmanL. M.SmithM. A.JensenC. C.YoshigiM.BlankmanE.UllmanK. S.et al (2020). Mechanical stress triggers nuclear remodeling and the formation of transmembrane actin nuclear lines with associated nuclear pore complexes. Mol. Biol. Cell.31 (16), 1774–1787. 10.1091/mbc.E19-01-0027
51
HsiehC.-L.ChaoP.-D. L.FangS.-H. (2005). Morin sulphates/glucuronides enhance macrophage function in microgravity culture system. Eur. J. Clin. Invest.35 (9), 591–596. 10.1111/j.1365-2362.2005.01551.x
52
HuangS.ShaoT.LiuH.WangQ.LiT.ZhaoQ. (2022). SIRT6 mediates MRTF-A deacetylation in vascular endothelial cells to antagonize oxLDL-induced ICAM-1 transcription. Cell. Death Discov.8 (1), 96–10. 10.1038/s41420-022-00903-y
53
Hughes-FulfordM.ChangT. T.MartinezE. M.LiC.-F. (2015). Spaceflight alters expression of microRNA during T-cell activation. FASEB J. official Publ. Fed. Am. Soc. Exp. Biol.29 (12), 4893–4900. 10.1096/fj.15-277392
54
IvashkivL. B. (2013). Epigenetic regulation of macrophage polarization and function. Trends Immunol.34 (5), 216–223. 10.1016/j.it.2012.11.001
55
JaaloukD. E.LammerdingJ. (2009). Mechanotransduction gone awry. Nat. Rev. Mol. Cell. Biol.10 (1), 63–73. 10.1038/nrm2597
56
JainN.MoellerJ.VogelV. (2019). Mechanobiology of macrophages: How physical factors coregulate macrophage plasticity and phagocytosis. Annu. Rev. Biomed. Eng.21 (1), 267–297. 10.1146/annurev-bioeng-062117-121224
57
JainN.VogelV. (2018). Spatial confinement downsizes the inflammatory response of macrophages. Nat. Mat.17 (12), 1134–1144. 10.1038/s41563-018-0190-6
58
JanmalekiM.PachenariM.SeyedpourS. M.ShahghadamiR.Sanati-NezhadA. (2016). Impact of simulated microgravity on cytoskeleton and viscoelastic properties of endothelial cell. Sci. Rep.6 (1), 32418. 10.1038/srep32418
59
KeX.ChenC.SongY.CaiQ.LiJ.TangY.et al (2019). Hypoxia modifies the polarization of macrophages and their inflammatory microenvironment, and inhibits malignant behavior in cancer cells. Oncol. Lett.18 (6), 5871–5878. 10.3892/ol.2019.10956
60
KimH.ShinY.KimD.-H. (2021). Mechanobiological implications of cancer progression in space. Front. Cell. Dev. Biol.9, 740009. 10.3389/fcell.2021.740009
61
KimJ. H.StuderR. K.VoN. V.SowaG. A.KangJ. D. (2009). p38 MAPK inhibition selectively mitigates inflammatory mediators and VEGF production in AF cells co-cultured with activated macrophage-like THP-1 cells. Osteoarthr. Cartil.12 (17), 1662–1669. 10.1016/j.joca.2009.06.004
62
KitchenG. B.CunninghamP. S.PoolmanT. M.IqbalM.MaidstoneR.BaxterM.et al (2020). The clock gene Bmal1 inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia. Proc. Natl. Acad. Sci. U. S. A.117 (3), 1543–1551. 10.1073/pnas.1915932117
63
KoboriT.HamasakiS.KitauraA.YamazakiY.NishinakaT.NiwaA.et al (2018). Interleukin-18 amplifies macrophage polarization and morphological alteration, leading to excessive angiogenesis. Front. Immunol.9, 334. 10.3389/fimmu.2018.00334
64
KohnF.HauslageJ.HankeW. (2017). Membrane fluidity changes, A basic mechanism of interaction of gravity with cells?Microgravity Sci. Technol.29 (5), 337–342. 10.1007/s12217-017-9552-y
65
KrawczykK. K.Yao MattissonI.EkmanM.OskolkovN.GrantingeR.KotowskaD.et al (2015). Myocardin family members drive formation of caveolae. PLoS ONE10 (8), e0133931. 10.1371/journal.pone.0133931
66
KrizajD.Toft-BertelsenT. L.gorusupudiA.MacaulayN.BernsteinP. S.LakkM. (2020). Cholesterol regulates TRPV4-dependent signaling in the trabecular meshwork. Investigative Ophthalmol. Vis. Sci.61 (7), 3424.
67
KuchlerO.GerlachJ.VomhofT.HettichJ.SteinmetzJ.GebhardtJ. C. M.et al (2022). Single-molecule tracking (SMT) and localization of SRF and MRTF transcription factors during neuronal stimulation and differentiation. Open Biol.12 (5), 210383. 10.1098/rsob.210383
68
Le RouxA.-L.QuirogaX.WalaniN.ArroyoM.Roca-CusachsP. (2019). The plasma membrane as a mechanochemical transducer. Philos. Trans. R. Soc. Lond. B Biol. Sci.374 (1779), 20180221. 10.1098/rstb.2018.0221
69
LeinhosL.PetersJ.KrullS.HelbigL.VoglerM.LevayM.et al (2019). Hypoxia suppresses myofibroblast differentiation by changing RhoA activity. J. Cell. Sci.132 (5), jcs223230. 10.1242/jcs.223230
70
LiC. X.TaleleN. P.BooS.KoehlerA.Knee-WaldenE.BalestriniJ. L.et al (2017). MicroRNA-21 preserves the fibrotic mechanical memory of mesenchymal stem cells. Nat. Mat.16 (3), 379–389. 10.1038/nmat4780
71
LiJ.ScherlA.MedinaF.FrankP. G.KitsisR. N.TanowitzH. B.et al (2005). Impaired phagocytosis in caveolin-1 deficient macrophages. Cell. CycleGeorget. Tex.)4 (11), 1599–1607. 10.4161/cc.4.11.2117
72
LinX.ZhangK.WeiD.TianY.GaoY.ChenZ.et al (2020). The impact of spaceflight and simulated microgravity on cell adhesion. Int. J. Mol. Sci.21 (9), 3031. 10.3390/ijms21093031
73
LiuH.ZhuL.DudikiT.GabanicB.GoodL.PodrezE. A.et al (2020). Macrophage migration and phagocytosis are controlled by kindlin-3’s link to the cytoskeleton. J. Immunol.204 (7), 1954–1967. 10.4049/jimmunol.1901134
74
LiuL.BankellE.RippeC.MorénB.StenkulaK. G.NilssonB.-O.et al (2021). Cell type dependent suppression of inflammatory mediators by myocardin related transcription factors. Front. Physiol.12, 732564. 10.3389/fphys.2021.732564
75
LiuL.LuoQ.SunJ.SongG. (2019). Cytoskeletal control of nuclear morphology and stiffness are required for OPN-induced bone-marrow-derived mesenchymal stem cell migration. Biochem. Cell. Biol.97 (4), 463–470. 10.1139/bcb-2018-0263
76
LiuL.WuX.XuH.YuL.ZhangX.LiL.et al (2018). Myocardin-related transcription factor A (MRTF-A) contributes to acute kidney injury by regulating macrophage ROS production. Biochim. Biophys. Acta. Mol. Basis Dis.1864 (10), 3109–3121. 10.1016/j.bbadis.2018.05.026
77
Lopez-HernandezA.SbernaS.CampanerS. (2021). Emerging principles in the transcriptional control by YAP and TAZ. Cancers13 (16), 4242. 10.3390/cancers13164242
78
LuX.YuY.TanS. (2020). The role of the miR-21-5p-mediated inflammatory pathway in ulcerative colitis. Exp. Ther. Med.19 (2), 981–989. 10.3892/etm.2019.8277
79
LudtkaC.MooreE.AllenJ. B. (2021a). The effects of simulated microgravity on macrophage phenotype. Biomedicines9 (9), 1205. 10.3390/biomedicines9091205
80
LudtkaC.SilbermanJ.MooreE.AllenJ. B. (2021b). Macrophages in microgravity: The impact of space on immune cells. npj Microgravity7 (1), 13–10. 10.1038/s41526-021-00141-z
81
MakM.KimT.ZamanM. H.KammR. D. (2015). Multiscale mechanobiology: Computational models for integrating molecules to multicellular systems. Integr. Biol.7 (10), 1093–1108. 10.1039/c5ib00043b
82
MaoX.ChenZ.LuoQ.ZhangB.SongG. (2016). Simulated microgravity inhibits the migration of mesenchymal stem cells by remodeling actin cytoskeleton and increasing cell stiffness. Cytotechnology68 (6), 2235–2243. 10.1007/s10616-016-0007-x
83
McGeeK. M.VartiainenM. K.KhawP. T.TreismanR.BaillyM. (2011). Nuclear transport of the serum response factor coactivator MRTF-A is downregulated at tensional homeostasis. EMBO Rep.12 (9), 963–970. 10.1038/embor.2011.141
84
McGregorA. L.HsiaC.-R.LammerdingJ. (2016). Squish and squeeze-the nucleus as a physical barrier during migration in confined environments. Curr. Opin. Cell. Biol.40, 32–40. 10.1016/j.ceb.2016.01.011
85
MeermanM.Bracco GartnerT. C. L.BuikemaJ. W.WuS. M.SiddiqiS.BoutenC. V. C.et al (2021). Myocardial disease and long-distance space travel: Solving the radiation problem. Front. Cardiovasc. Med.8, 631985. 10.3389/fcvm.2021.631985
86
MeizlishM. L. (2021). Macrophage mechanosensing of the tissue environment and signal integration through the cytoskeleton. Ph.D. Yale University. Available at: https://www.proquest.com/docview/2557411531/abstract/4AF34E8444E0469APQ/1 (Accessed September 25, 2021).
87
MeloniM. A.GalleriG.PaniG.SabaA.PippiaP.Cogoli-GreuterM. (2011). Space flight affects motility and cytoskeletal structures in human monocyte cell line J-111. Cytoskeleton68 (2), 125–137. 10.1002/cm.20499
88
MeloniM. A.GalleriG.PippiaP.Cogoli-GreuterM. (2006). Cytoskeleton changes and impaired motility of monocytes at modelled low gravity. Protoplasma229 (2–4), 243–249. 10.1007/s00709-006-0210-2
89
MerchedA. J.WilliamsE.ChanL. (2003). Macrophage-specific p53 expression plays a crucial role in atherosclerosis development and plaque remodeling. Arterioscler. Thromb. Vasc. Biol.23 (9), 1608–1614. 10.1161/01.ATV.0000084825.88022.53
90
MezianiL.DeutschE.MondiniM. (2018). Macrophages in radiation injury: A new therapeutic target. Oncoimmunology7 (10), e1494488. 10.1080/2162402X.2018.1494488
91
MierkeC. T. (2021). The pertinent role of cell and matrix mechanics in cell adhesion and migration. Front. Cell. Dev. Biol.9, 720494. 10.3389/fcell.2021.720494
92
MirandaM. Z.LichnerZ.SzásziK.KapusA. (2021). Mrtf: Basic biology and role in kidney disease. Int. J. Mol. Sci.22 (11), 6040. 10.3390/ijms22116040
93
MorrisonT. E.KenneyS. C. (2004). BZLF1, an Epstein-Barr virus immediate-early protein, induces p65 nuclear translocation while inhibiting p65 transcriptional function. Virology328 (2), 219–232. 10.1016/j.virol.2004.07.020
94
MuJ. (2018). RhoA signaling in CCL2-induced macrophage polarization. J. Allergy Clin. Immunol.141 (2), AB114. 10.1016/j.jaci.2017.12.363
95
MukherjeeP.RahamanS. G.GoswamiR.DuttaB.MahantyM.RahamanS. O. (2022). Role of mechanosensitive channels/receptors in atherosclerosis. Am. J. Physiol. Cell. Physiol.322 (5), C927–C938. 10.1152/ajpcell.00396.2021
96
NabaviN.KhandaniA.CamirandA.HarrisonR. E. (2011). Effects of microgravity on osteoclast bone resorption and osteoblast cytoskeletal organization and adhesion. Bone49 (5), 965–974. 10.1016/j.bone.2011.07.036
97
NeelamS.RichardsonB.BarkerR.UdaveC.GilroyS.CameronM. J.et al (2020). Changes in nuclear shape and gene expression in response to simulated microgravity are LINC complex-dependent. Int. J. Mol. Sci.21 (18), 6762. 10.3390/ijms21186762
98
OlsonE. N.NordheimA. (2010). Linking actin dynamics and gene transcription to drive cellular motile functions. Nat. Rev. Mol. Cell. Biol.11 (5), 353–365. 10.1038/nrm2890
99
OrsiniE. M.PerelasA.SouthernB. D.GroveL. M.OlmanM. A.ScheragaR. G. (2021). Stretching the function of innate immune cells. Front. Immunol.0, 767319. 10.3389/fimmu.2021.767319
100
PaardekooperL. M.BendixM. B.OttriaA.de HaerL. W.ter BeestM.RadstakeT. R. D. J.et al (2018). Hypoxia potentiates monocyte-derived dendritic cells for release of tumor necrosis factor α via MAP3K8. Biosci. Rep.38 (6), BSR20182019. 10.1042/BSR20182019
101
PanayiotouR.MirallesF.PawlowskiR.DiringJ.FlynnH. R.SkehelM.et al (2016). Phosphorylation acts positively and negatively to regulate MRTF-A subcellular localisation and activity. eLife5, e15460. 10.7554/eLife.15460
102
PapaseitC.PochonN.TabonyJ. (2000). Microtubule self-organization is gravity-dependent. Proc. Natl. Acad. Sci. U. S. A.97 (15), 8364–8368. 10.1073/pnas.140029597
103
PatelS. (2020). The effects of microgravity and space radiation on cardiovascular health: From low-Earth orbit and beyond. Int. J. Cardiol. Heart Vasc.30, 100595. 10.1016/j.ijcha.2020.100595
104
PathakM. M.TranT.HongL.JoósB.MorrisC. E.TombolaF. (2016). The Hv1 proton channel responds to mechanical stimuli. J. Gen. Physiol.148 (5), 405–418. 10.1085/jgp.201611672
105
PaulsenK.TauberS.DumreseC.BradacsG.SimmetD. M.GölzN.et al (2015). Regulation of ICAM-1 in cells of the monocyte/macrophage system in microgravity. Biomed. Res. Int.2015, e538786. 10.1155/2015/538786
106
PaulsenK.TauberS.GoelzN.SimmetD. M.EngeliS.BirlemM.et al (2014). Severe disruption of the cytoskeleton and immunologically relevant surface molecules in a human macrophageal cell line in microgravity—results of an in vitro experiment on board of the shenzhou-8 space mission. Acta Astronaut.94 (1), 277–292. 10.1016/j.actaastro.2013.06.007
107
PoonC. (2020). Factors implicating the validity and interpretation of mechanobiology studies in simulated microgravity environments. Eng. Rep.2 (10), e12242. 10.1002/eng2.12242
108
QiY.-X.YaoQ.-P.HuangK.ShiQ.ZhangP.WangG.-L.et al (2016). Nuclear envelope proteins modulate proliferation of vascular smooth muscle cells during cyclic stretch application. Proc. Natl. Acad. Sci. U. S. A.113 (19), 5293–5298. 10.1073/pnas.1604569113
109
RahamanS. O.GroveL. M.ParuchuriS.SouthernB. D.AbrahamS.NieseK. A.et al (2014). TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice. J. Clin. Invest.124 (12), 5225–5238. 10.1172/JCI75331
110
RamseyI. S.RuchtiE.KaczmarekJ. S.ClaphamD. E. (2009). Hv1 proton channels are required for high-level NADPH oxidase-dependent superoxide production during the phagocyte respiratory burst. Proc. Natl. Acad. Sci. U. S. A.106 (18), 7642–7647. 10.1073/pnas.0902761106
111
RanF.AnL.FanY.HangH.WangS. (2016). Simulated microgravity potentiates generation of reactive oxygen species in cells. Biophys. Rep.2 (5), 100–105. 10.1007/s41048-016-0029-0
112
RecordJ.SaeedM. B.VenitT.PercipalleP.WesterbergL. S. (2021). Journey to the center of the cell: Cytoplasmic and nuclear actin in immune cell functions. Front. Cell. Dev. Biol.9, 682294. 10.3389/fcell.2021.682294
113
RomeroL. O.MasseyA. E.Mata-DaboinA. D.Sierra-ValdezF. J.ChauhanS. C.Cordero-MoralesJ. F.et al (2019). Dietary fatty acids fine-tune Piezo1 mechanical response. Nat. Commun.10 (1), 1200. 10.1038/s41467-019-09055-7
114
RonkinaN.LaferaJ.KotlyarovA.GaestelM. (2016). Stress-dependent phosphorylation of myocardin-related transcription factor A (MRTF-A) by the p38(MAPK)/MK2 axis. Sci. Rep.6, 31219. 10.1038/srep31219
115
RonzierE.LaurensonA. J.ManickamR.LiuS.SaintilmaI. M.SchrockD. C.et al (2022). The actin cytoskeleton responds to inflammatory cues and alters macrophage activation. Cells11 (11), 1806. 10.3390/cells11111806
116
RubioJ. M.AstudilloA. M.CasasJ.BalboaM. A.BalsindeJ. (2018). Regulation of phagocytosis in macrophages by membrane ethanolamine plasmalogens. Front. Immunol.9, 1723. 10.3389/fimmu.2018.01723
117
SakaiY.YamamoriT.YoshikawaY.BoT.SuzukiM.YamamotoK.et al (2018). NADPH oxidase 4 mediates ROS production in radiation-induced senescent cells and promotes migration of inflammatory cells. Free Radic. Res.52 (1), 92–102. 10.1080/10715762.2017.1416112
118
SchaeferA.Te RietJ.RitzK.HoogenboezemM.AnthonyE. C.MulF. P. J.et al (2014). Actin-binding proteins differentially regulate endothelial cell stiffness, ICAM-1 function and neutrophil transmigration. J. Cell. Sci.127 (20), 4470–4482. 10.1242/jcs.154708
119
SchuchK.WankoB.AmbrozK.Castelo-RosaA.Moreno-ViedmaV.GrünN. G.et al (2016). Osteopontin affects macrophage polarization promoting endocytic but not inflammatory properties. Obesity24 (7), 1489–1498. 10.1002/oby.21510
120
ShanmugarajanS.ZhangY.Moreno-VillanuevaM.ClantonR.RohdeL. H.RameshG. T.et al (2017). Combined effects of simulated microgravity and radiation exposure on osteoclast cell fusion. Int. J. Mol. Sci.18 (11), 2443. 10.3390/ijms18112443
121
SharmaS.GoswamiR.MerthM.CohenJ.LeiK. Y.ZhangD. X.et al (2017). TRPV4 ion channel is a novel regulator of dermal myofibroblast differentiation. Am. J. Physiol. Cell. Physiol.312 (5), C562–C572. 10.1152/ajpcell.00187.2016
122
ShiL.TianH.WangP.LiL.ZhangZ.ZhangJ.et al (2021). Spaceflight and simulated microgravity suppresses macrophage development via altered RAS/ERK/NFκB and metabolic pathways. Cell. Mol. Immunol.18 (6), 1489–1502. 10.1038/s41423-019-0346-6
123
ShiratoK.SatoS. (2022). Macrophage meets the circadian clock: Implication of the circadian clock in the role of macrophages in acute lower respiratory tract infection. Front. Cell. Infect. Microbiol.12, 826738. 10.3389/fcimb.2022.826738
124
SianatiS.SchroeterL.RichardsonJ.TayA.LamandéS. R.PooleK. (2021). Modulating the mechanical activation of TRPV4 at the cell-substrate interface. Front. Bioeng. Biotechnol.8, 608951. 10.3389/fbioe.2020.608951
125
SidorenkoE.SokolovaM.PennanenA. P.KyheröinenS.PosernG.FoisnerR.et al (2022). Lamina-associated polypeptide 2α is required for intranuclear MRTF-A activity. Sci. Rep.12 (1), 2306. 10.1038/s41598-022-06135-5
126
SimmetD. M.SchwarzwalderA.PaulsenK.TauberS.EngelmannF.ThielC. S. (2013). Biotechnology for the investigation of the monocyte-macrophage-system in microgravity and space. Recent Adv. Space Biotech.3 (1), 48–63. 10.2174/18776112029990012
127
SmithJ. K. (2020). Microgravity, bone homeostasis, and insulin-like growth factor-1. Appl. Sci.10 (13), 4433. 10.3390/app10134433
128
SmithJ. T.WilleyN. J.HancockJ. T. (2012). Low dose ionizing radiation produces too few reactive oxygen species to directly affect antioxidant concentrations in cells. Biol. Lett.8 (4), 594–597. 10.1098/rsbl.2012.0150
129
SpeightP.KoflerM.SzásziK.KapusA. (2016). Context-dependent switch in chemo/mechanotransduction via multilevel crosstalk among cytoskeleton-regulated MRTF and TAZ and TGFβ-regulated Smad3. Nat. Commun.7 (1), 11642. 10.1038/ncomms11642
130
SprenkelerE. G. G.GuentherC.FaisalI.KuijpersT. W.FagerholmS. C. (2021). Molecular mechanisms of leukocyte migration and its potential targeting-lessons learned from MKL1/SRF-related primary immunodeficiency diseases. Front. Immunol.12, 615477. 10.3389/fimmu.2021.615477
131
SullivanA. L.BennerC.HeinzS.HuangW.XieL.MianoJ. M.et al (2011). Serum response factor utilizes distinct promoter- and enhancer-based mechanisms to regulate cytoskeletal gene expression in macrophages. Mol. Cell. Biol.31 (4), 861–875. 10.1128/MCB.00836-10
132
SunW.ChiS.LiY.LingS.TanY.XuY.et al (2019). in The mechanosensitive Piezo1 channel is required for bone formation. Editors RosenC. J.DietzH. C.SherkV., 8, e47454. N.A. Haelterman, eLife. 10.7554/eLife.47454
133
SunY.KuangY.ZuoZ. (2021). The emerging role of macrophages in immune system dysfunction under real and simulated microgravity conditions. Int. J. Mol. Sci.22 (5), 2333. 10.3390/ijms22052333
134
TauberS.LauberB. A.PaulsenK.LayerL. E.LehmannM.HauschildS.et al (2017). Cytoskeletal stability and metabolic alterations in primary human macrophages in long-term microgravity. PLOS ONE12 (4), e0175599. 10.1371/journal.pone.0175599
135
ThielC. S.de ZélicourtD.TauberS.AdrianA.FranzM.SimmetD. M.et al (2017). Rapid adaptation to microgravity in mammalian macrophage cells. Sci. Rep.7 (1), 43. 10.1038/s41598-017-00119-6
136
ThielC. S.TauberS.LauberB.PolzerJ.SeebacherC.UhlR.et al (2019). Rapid morphological and cytoskeletal response to microgravity in human primary macrophages. Int. J. Mol. Sci.20 (10), 2402. 10.3390/ijms20102402
137
ThielC. S.VahlensieckC.BradleyT.TauberS.LehmannM.UllrichO. (2021). Metabolic dynamics in short- and long-term microgravity in human primary macrophages. Int. J. Mol. Sci.22 (13), 6752. 10.3390/ijms22136752
138
ThompsonM.WoodsK.NewbergJ.OxfordJ. T.UzerG. (2020). Low-intensity vibration restores nuclear YAP levels and acute YAP nuclear shuttling in mesenchymal stem cells subjected to simulated microgravity. npj Microgravity6 (1), 35–11. 10.1038/s41526-020-00125-5
139
TilghmanR. W.HooverR. L. (2002). E-selectin and ICAM-1 are incorporated into detergent-insoluble membrane domains following clustering in endothelial cells. FEBS Lett.525 (1–3), 83–87. 10.1016/s0014-5793(02)03070-3
140
VahlensieckC.ThielC. S.PöschlD.BradleyT.KrammerS.LauberB.et al (2022). Post-transcriptional dynamics is involved in rapid adaptation to hypergravity in jurkat T cells. Front. Cell. Dev. Biol.10, 933984. 10.3389/fcell.2022.933984
141
VelasquezL. S.SutherlandL. B.LiuZ.GrinnellF.KammK. E.SchneiderJ. W.et al (2013). Activation of MRTF-A–dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing. Proc. Natl. Acad. Sci. U. S. A.110 (42), 16850–16855. 10.1073/pnas.1316764110
142
VenitT.El SaidN. H.MahmoodS. R.PercipalleP. (2021). A dynamic actin-dependent nucleoskeleton and cell identity. J. Biochem.169 (3), 243–257. 10.1093/jb/mvaa133
143
VogelJ.ThielC. S.TauberS.StockmannC.GassmannM.UllrichO. (2019). Expression of hypoxia-inducible factor 1α (HIF-1α) and genes of related pathways in altered gravity. Int. J. Mol. Sci.20 (2), 436. 10.3390/ijms20020436
144
WangC.ChenH.LuoH.ZhuL.ZhaoY.TianH.et al (2015). Microgravity activates p38 MAPK-C/EBPβ pathway to regulate the expression of arginase and inflammatory cytokines in macrophages. Inflamm. Res.64 (5), 303–311. 10.1007/s00011-015-0811-3
145
WangC.LuoH.ZhuL.YangF.ChuZ.TianH.et al (2014). Microgravity inhibition of lipopolysaccharide-induced tumor necrosis factor-α expression in macrophage cells. Inflamm. Res.63 (1), 91–98. 10.1007/s00011-013-0676-2
146
WangJ.HanC.LuZ.GeP.CuiY.ZhaoD.et al (2020). Simulated microgravity suppresses MAPK pathway-mediated innate immune response to bacterial infection and induces gut microbiota dysbiosis. FASEB J.34 (11), 14631–14644. 10.1096/fj.202001428R
147
WangY.WangG. Z.RabinovitchP. S.TabasI. (2014). Macrophage mitochondrial oxidative stress promotes atherosclerosis and nuclear factor-κb–mediated inflammation in macrophages. Circ. Res.114 (3), 421–433. 10.1161/CIRCRESAHA.114.302153
148
WangZ.BrandtS.MedeirosA.WangS.WuH.DentA.et al (2015). MicroRNA 21 is a homeostatic regulator of macrophage polarization and prevents prostaglandin E2-mediated M2 generation. PLoS ONE10 (2), e0115855. 10.1371/journal.pone.0115855
149
WuQ.AllouchA.MartinsI.ModjtahediN.DeutschE.PerfettiniJ.-L. (2017). Macrophage biology plays a central role during ionizing radiation-elicited tumor response. Biomed. J.40 (4), 200–211. 10.1016/j.bj.2017.06.003
150
WubshetN. H.Arreguin-MartinezE.NailM.AnnamalaiH.KoernerR.RoussevaM.et al (2021). Simulating microgravity using a random positioning machine for inducing cellular responses to mechanotransduction in human osteoblasts. Rev. Sci. Instrum.92 (11), 114101. 10.1063/5.0056366
151
XiongX.LiW.NamJ.MaK. (2021). Integrin signaling via actin cytoskeleton activates MRTF/SRF to entrain circadian clock. bioRxiv2021, 456061. 08.12. 10.1101/2021.08.12.456061
152
YangP.-Y.AlmoftiM. R.LuL.KangH.ZhangJ.LiT.-J.et al (2005). Reduction of atherosclerosis in cholesterol-fed rabbits and decrease of expressions of intracellular adhesion molecule-1 and vascular endothelial growth factor in foam cells by a water-soluble fraction of polygonum multiflorum. J. Pharmacol. Sci.99 (3), 294–300. 10.1254/jphs.FP0050333
153
YangX.SunL.-W.DuC.-F.WuX.-T.FanY.-B. (2018). Finite element analysis of osteocytes mechanosensitivity under simulated microgravity. Microgravity Sci. Technol.30 (4), 469–481. 10.1007/s12217-018-9613-x
154
YangY.YangG.YuL.LinL.LiuL.FangM.et al (2020). An interplay between MRTF-A and the histone acetyltransferase TIP60 mediates hypoxia-reoxygenation induced iNOS transcription in macrophages. Front. Cell. Dev. Biol.8, 484. 10.3389/fcell.2020.00484
155
YuL.WengX.LiangP.DaiX.WuX.XuH.et al (2014). MRTF-A mediates LPS-induced pro-inflammatory transcription by interacting with the COMPASS complex. J. Cell. Sci.127 (21), 4645–4657. 10.1242/jcs.152314
156
Yu-Wai-ManC.Spencer-DeneB.LeeR. M. H.HutchingsK.LisabethE. M.TreismanR.et al (2017). Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis. Sci. Rep.7 (1), 518. 10.1038/s41598-017-00212-w
157
ZarembaT.G.IrwinR. D. (1981). Effects of ionizing radiation on the polymerization of microtubules in vitro. Biochem.20 (5), 1323–1332. 10.1021/bi00508a044
158
ZhangL.LiH.-L.ZhangD.-D.CuiX.-C. (2021). Therapeutic effects of myocardin-related transcription factor A (MRTF-A) knockout on experimental mice with nonalcoholic steatohepatitis induced by high-fat diet. Hum. Exp. Toxicol.40 (10), 1634–1645. 10.1177/09603271211002886
159
ZhangM.GaoJ.ZhaoX.ZhaoM.MaD.ZhangX.et al (2021). p38α in macrophages aggravates arterial endothelium injury by releasing IL-6 through phosphorylating megakaryocytic leukemia 1. Redox Biol.38, 101775. 10.1016/j.redox.2020.101775
160
ZhongH.LinH.PangQ.ZhuangJ.LiuX.LiX.et al (2021). Macrophage ICAM-1 functions as a regulator of phagocytosis in LPS induced endotoxemia. Inflamm. Res.70 (2), 193–203. 10.1007/s00011-021-01437-2
161
ZhouH.XueY.DongL.WangC. (2021). Biomaterial-based physical regulation of macrophage behaviour. J. Mat. Chem. B9 (17), 3608–3621. 10.1039/D1TB00107H
Summary
Keywords
mechanobiology, microgravity, macrophage, multiscale, MRTF, radiation
Citation
An R (2022) MRTF may be the missing link in a multiscale mechanobiology approach toward macrophage dysfunction in space. Front. Cell Dev. Biol. 10:997365. doi: 10.3389/fcell.2022.997365
Received
18 July 2022
Accepted
10 August 2022
Published
12 September 2022
Volume
10 - 2022
Edited by
Claudia Tanja Mierke, Leipzig University, Germany
Updates
Copyright
© 2022 An.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Rocky An, ra474@cornell.edu
This article was submitted to Cell Adhesion and Migration, a section of the journal Frontiers in Cell and Developmental Biology
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.