Biology of Interleukin-17 and Its Pathophysiological Significance in Sepsis

The interleukin (IL)-17 family includes six structure-related cytokines (A–F). To date, majority of studies have focused on IL-17A. IL-17A plays a pivotal role in various infectious diseases, inflammatory and autoimmune disorders, and cancer. Several recent studies have indicated that IL-17A is a biomarker as well as a therapeutic target in sepsis. In the current review, we summarize the biological functions of IL-17, including IL-17-mediated responses and signal transduction pathways, with particular emphasis on clinical relevance to sepsis.

IL-17A expression was first reported in T helper (Th) cells (10,11). IL-17A is recognized as a hallmark molecule of CD4 + T helper 17 (Th17) cells, which characteristically express the transcription factor RAR-related orphan receptor γ (RORγt) (12). The development of Th17 cells, including clonal expansion and phenotype stabilization of IL-17A production, is dependent on IL-23 (13). Mechanistically, IL-23 expands the Th17 cell population by upregulating signal transducers and activators of transcription (STAT)-triggered RORγt and subsequent promotion of IL-17A release (14). Thus, IL-23 is recognized as a potent inducer of IL-17A. Recent studies suggest that the so-called "IL-17/IL-23 axis" is a key element in inflammation and is involved in the immune responses to fungal and bacterial infection and autoimmune diseases (12,13). IL-17A can be secreted by other cell subsets, such as γδT cells, cytotoxic CD8 + T cells, innate tissue-specific cells, innate lymphoid cells (ILCs), and myeloid cells (Figure 2) (14,15). IL-17A-mediated inflammation is required for host protection and survival against infection (8,9,16). IL-17A can also exacerbate fetal inflammatory responses, and has been implicated in immunopathology. IL-17A levels are elevated in various inflammatory conditions, including sepsis, pneumonia, systemic lupus erythematosus, rheumatoid arthritis, allograft rejection, and cancer (17,18). Here we review the literature on IL-17-driven inflammatory and immune cascades during the development of sepsis.

IL-17 BIOLOGY Structural Features of IL-17
The IL-17 family contains six isoforms of 20-30 kDa molecular weight and is a group of secreted and glycosylated proteins. All other members of the IL-17 family show 20-55% sequence homology to IL-17A, with IL-17E exhibiting the lowest homology with other family members (8,9). IL-17A and IL-17F could exist as heterodimers or homodimers and are co-expressed by linked genes (19). Structurally, IL-17 family proteins have a conserved C-terminus with four cysteine residues, which form intramolecular disulfide bridges (20).
Th17 cells were first identified in 2005 and were recognized as the primary source of IL-17 (16). In addition to IL-17, Th17 cells also produce a variety of inflammatory cytokines including granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-21, and IL-22 (16). Th17-induced responses are implicated in host defense against infections, inflammatory and autoimmune disorders, and tumorigenesis (21). Other major sources of IL-17 include myeloid cells (e.g., kidneys and lungs) and Paneth cells in the intestinal crypts (8).
In response to stress proteins, pathogen-associated molecular patterns (PAMPs), or microbial metabolites, antigen-presenting cells (APCs) produce IL-23 and IL-1β to accelerate IL-17 release (8). IL-17 levels are depended on the particular context, including the pathogen and site and severity of infection (10,12).

IL-17 Receptor and Its Signal Transduction
IL-17 cytokines bind to five cytokine receptors (IL-17RA to IL-17RE, Figure 2) on target cells to drive their biological actions (2,9). IL-17R is expressed in a variety of cell populations, including keratinocytes, fibroblasts, mesothelial cells, epithelial cells, and leukocytes (9). All these receptors share a SEFIR domain in the intracellular domain and a fibronectin III-like region in FIGURE 2 | Cellular sources and receptors of interleukin-17. Interleukin (IL)-17 family includes isoforms A to F. IL-17 can be induced by a variety of cells including T helper (Th) 17 cells, γδT cells, natural killer T (NKT) cells, group 3 innate lymphoid cells (ILC3s), CD8 + (Tc17) cells, neutrophils, microglia, mast cells, myeloid cells in the lung and kidneys, and Paneth cells in the intestine. In addition, antigen-presenting cells (APCs) stimulate the production of IL-17in response to stress proteins, pathogen-associated molecular patterns (PAMPs), or microbial metabolites. IL-17 receptor (IL-17R) family is composed of IL-17RA, IL-17RB, IL-17RC, IL-17RE, as well as IL-17RA and C heterodimeric complex.
Studies suggest that IL-17RD also drives IL-17-mediated signaling, but the ligand of IL-17RD remains unknown (21).
IL-17A is critical for maintaining mucosal barrier integrity and function by increasing tight junctions and inducing acute phase proteins (8,9). IL-17A helps to orchestrate airway vascular remodeling through Th17 cell responses in pulmonary inflammation (8). Similarly, IL-17A has been shown to upregulate endothelial tissue factor and is involved in splenic vein remodeling (30). Additionally, IL-17A plays a key role in repair and remodeling of other tissues such as ventricular tissue in myocardial infarction and bone resorption (31).

Roles of IL-17B Through IL-17F
IL-17B was originally identified as a proinflammatory mediator that accelerates neutrophil recruitment and migration (7). IL-17B inhibits IL-25 signaling and attenuates mucosal inflammation (5). IL-17B promotes the proliferation and survival of cancer cells in animal models (7), and increased IL-17B levels are linked to poor outcome in patients with several types of cancers (e.g., breast, lung, and pancreatic) (5).
IL-17C can be produced by several non-immune cells (e.g., epithelial cells, cutaneous neurons, and keratinocytes) and provide host protection in the intestine, skin, and the nervous system (5). For example, IL-17C released from epithelial cells FIGURE 3 | Interleukin-17A signaling transduction pathway. In general, all IL-17R members contain a shared and conserved cytoplasmic motif named a SEFIR/SEFEX domain similar to the TIR region in IL-1 receptors and TLRs. Initially, IL-17R signaling triggers the recruitment of Act1, which includes a SEFIR domain and is required for IL-17R-Act1 combination. Subsequently, Act1 can ubiquitinate TRAF6 and E3 ubiquitin ligase. Upon ligand binding, TRAF2/5, TRAF4, and TRAF6 can be engaged by Act1 and stabilize mRNAs by activating RNA-binding proteins such as Arid5a, HuR, and DDX3X. IL-17A promotes the activities of AP1 and MAPK, as well as δ transcription factors and C/EBPβ activation (CBAD). IL-17A also accelerates IκBα degradation and IKK activation, thereby inducing NF-κB signaling. NF-κB in turn improves IL-17A-mediated proinflammatory and anti-microbial responses. IL-17A/NF-κB signal transduction can trigger a feedback loop that controls overactivation of the NF-κB cascade. TRAF, TNF-receptor associated factor; SEFIR, similar expression of fibroblast growth factor and IL-17Rs; SEFEX, SEFIR extension; TLRs, Toll-like receptors; C/EBPβ, CCAAT/enhancer-binding protein β; CBAD, C/EBPβ activation domain; AP1, activator protein 1; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor κB; IKK, IκBα degradation and IκB kinase; JNK, Janus kinase; HuR, human antigen R. maintains barrier integrity in an autocrine manner following epithelial damage (8). Emerging evidence indicates that IL-17C is sufficient to promote growth and survival of nerves and protect peripheral neurons during reactivation of herpes simplex virus-2 (6).
IL-17D is the least studied cytokine in the IL-17 family. Similar to other isoforms, IL-17D triggers secretion of diverse inflammatory cytokines such as GM-CSF, IL-6, and IL-8. Several studies have shown markedly increased IL-17D in viral infection and tumors (7).
IL-17F and IL-17A share similarities in receptors, signaling, function, and cellular sources. Similar to IL-17A, IL-17F plays a critical role in inflammatory responses and mucosal barrier maintenance (4).
confers powerful protective effects against infections caused by bacteria, fungi, virus, and parasites ( Figure 5); (Table 1) (16,17). Increased circulating levels of IL-17A are observed in experimental and human sepsis (16,17). A series of clinical studies have demonstrated that high serum IL-17A levels are associated with greater risk of sepsis, suggesting that this cytokine might serve as a novel predictor of sepsis progression as well as an attractive therapeutic target (34).

Bacterial Infection
It is widely accepted that bacterial infections predominantly contribute to the development of sepsis (18). Interestingly, IL-17A genetic variations influence the risk of gram-positive infection and correlate with short-term mortality in patients with severe sepsis (55). Studies suggest that IL-17A-mediated signaling orchestrates inflammatory and immune cascades by inducing proinflammatory mediators, thereby participating in preventing bacteria during sepsis (21).
IL-17A levels are positively associated with tissue bacterial loads in mice infected with Klebsiella pneumonia (62). Physiological levels of IL-17A in type 3 innate lymphoid cells (ILCs) accelerate G-GSF production and neutrophil recruitment, protecting the host against sepsis (15). Experimental and human sepsis involves impaired neutrophil recruitment and migration, the extent of which is positively associated with disease severity (63). IL-17A augments the migration and microbicidal activity of neutrophils, as well as mobilization of T lymphocytes (64). IL-17A improves neutrophil recruitment and bacterial eradication via γδT cells in a murine model of sepsis (36).
Decreased levels of IL-17A are correlated with increased risk of bacteremia (62). In IL-17R-deficient mice infected with Klebsiella pneumoniae, levels of G-CSF, macrophage inflammatory protein-2 (MIP-2), and chemokines were reduced, contributing to decreased neutrophil infiltration and microbial clearance (62). In agreement with this observation, IL-17Adeficient mice are also more susceptible to infection by other bacteria, including Bordetella pertussis, Citrobacter rodentium, FIGURE 5 | Protective and pathological roles of interleukin-17A in the pathogenesis of sepsis. IL-17A triggers various immune cells (e.g., neutrophils, lymphocytes, macrophages, monocytes, and B cells) to boost innate, adaptive, and humoral responses with different actions. Meanwhile, IL-17A signaling exhibits a strong protective effect against diverse infections (e.g., bacterial, fungal, viral, and parasitic infections) through promotion of host defenses and cytokine release. In addition, IL-17A may induce pathologic immune responses and then impair organ functions, which result in pathological alterations such as acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), hepatic dysfunction, immune dysfunction, gut barrier dysfunction, and cardiomyocyte dysfunction.

Fungal Infection
Invasive fungal infection is increasingly frequent in septic patients and correlates with a high risk of mortality (70).

Viral Infection
Sepsis often occurs in cases of immunosuppression, when it manifests as an increased susceptibility to opportunistic infections, especially by virus (18). Several studies have shown that IL-17 promotes host immunity against influenza infection (21). In mice challenged with influenza virus, lack of IL-17 was associated with increased mortality (79). Adoptive transfer of IL-17-producing cells protected mice against a lethal dose of influenza virus (80). Also, IL-17A participates in the immunopathogenesis of influenza A (H1N1)-induced acute lung injury (80). Likely, IL-17Amediated response is correlated with disease severity following infections by Epstein-Barr virus (EBV), herpes simplex virus (HSV), respiratory syncytial virus (RSV), vaccinia virus, and hepatitis virus (81,82). Depletion of IL-17R mitigates inflammation and decreases neutrophil influx, hindering influenza infection (82). IL-17A neutralization could reduce viral load and mortality during herpes simplex virus infection (82). Protective or pathological roles of IL-17 during viral infections remain controversial.

Parasitic Infection
Few studies have examined the potential role of IL-17A in host defense against parasites (5). Studies suggest that Th17 cells, the major source of IL-17A, could impair host defenses against Echinococcus granulosus, Leishmania braziliensis, Toxoplasma gondii, and Trypanosoma cruzi (83)(84)(85)(86)(87). In patients with toxoplasmosis, CD8 + and CD4 + cells could limit parasitic replication and invasion (86). High IL-17A levels are detectable in peripheral blood mononuclear cells from patients with Leishmaniasis (87). IL-17R deficiency leads to lower expression of CXCL1 and CXCL2 in the liver and spleen as well as less neutrophil recruitment in Trypanosoma cruzi-infected mice (83). In the case of Leishmania infection, IL-17A blockade reduces disease severity in a mouse model (88). IL-17A antibody neutralization reduces inflammation and improves survival in mice following Toxoplasma gondii challenge (86). Collectively, available evidence supports a pathological role for IL-17 in parasitic infections, but further work is needed to explore whether this depends on the host, parasite, or other factors. In summary, IL-17 contributes to host protection against diverse infectious organisms during sepsis while inducing hyperinflammation with detrimental outcomes for the host under certain conditions. Further investigation on the role of IL-17 and the interplay with other immune factors needs to be conducted in clinical settings.

IL-17 in Organ Dysfunction Resulted From Sepsis
Studies have shown that overproduction of IL-17 could exaggerate immune responses, which in turn may lead to impaired organ function (89) (Figure 5). In line with these observations, elevated levels of IL-17A have been detected in plasma and tissues during sepsis associated with multiple organ damage (37,38,54,(56)(57)(58)61) (Table 1).

Acute Lung Injury or Acute Respiratory Distress Syndrome
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are early events in the course of sepsis (90). Neutrophil infiltration plays an integral part in ARDS. IL-17R signaling is proposed to regulate neutrophil trafficking into the lung to maintain host immunity (9). The addition of recombinant IL-17A into the airway causes the production of chemokines that recruit inflammatory and immune cells (48). In contrast, IL-17RA or IL-17A knockout decreases CXCL1 and G-CSF levels in the bronchoalveolar lavage fluid of mice (62). In line with this, hyperproduction of IL-17A is involved in uncontrolled pulmonary inflammation in mice infected with Haemophilus influenza (91). Interestingly, γδT lymphocytes (comprising the Vγ4 T lymphocytes) accumulate in the lungs of septic mice (46). Surprisingly, administration of anti-Vγ4 monoclonal antibody increased the mortality induced by CLP in septic mice (13,46). In mice with lipopolysaccharide-induced ARDS, levels of IL-17A were elevated in plasma, lung tissue lysate, and bronchoalveolar lavage fluid (60). Consistently, patients with sepsis-induced ARDS show persisting high levels of IL-17A, suggesting that IL-17A is a biomarker to assess the severity and prognosis of diseases (60). Moreover, activation of the IL-23/IL-17 signaling produces harmful effects on sepsis-driven lung inflammation (45). Specifically, IL-17A expression, known to be induced by IL-23, is significantly increased in the lungs of septic mice induced by CLP (45). Neutralization of IL-17A ameliorates ALI and ARDS by modulating PI3K signaling and RORγt expression (60), suggesting that IL-17 could be explored as a therapeutic target for sepsis-associated ARDS.

Immune Dysfunction or Immunosuppression
Sepsis disrupts immune homeostasis (64). A study in septic patients showed that inhibition of IL-17A by specific antibodies could lead to immune depression by increasing IL-10 release and decreasing IL-12 production from peripheral blood mononuclear cells (57).
Toxic shock syndrome caused by Streptococcal and Staphylococcal superantigens mimicks sepsis in clinical presentation. It is characterized by overexpression of proinflammatory cytokines and pathological immune responses (53). Overproduction of IL-17A was observed in the early phase of toxic shock syndrome; in contrast, anti-IL-17A antibodies obviously reduced intestinal and hepatic impairment and mortality rate (53).

Acute Kidney Injury
Acute kidney injury (AKI) is the hallmark and a risk factor of sepsis; reversal of AKI correlates with lower risk of mortality (89). Several experimental and clinical studies support the importance of IL-17A secretion in AKI (51). Strikingly, IL-17A can function as a chemokine that recruits neutrophils to the kidneys (55).
IL-17A is associated with elevated levels of proinflammatory cytokines and accelerated tubular epithelial apoptosis in AKI (51). IL-17A is upregulated in animal models of acute tubular injury and cisplatin-induced AKI (59). In Th17 cells stimulated by heat-killed C. albicans, IL-17A levels significantly increased in patients with AKI after sepsis compared with healthy counterparts (92). In one study, Th17 cell activation was higher in patients who died from AKI following sepsis than in survivors, and the extent of activation correlated with AKI-associated inflammation (93). IL-17A knockdown can mitigate interstitial neutrophil infiltration and tubular impairment (51,59). The intracellular receptor RORγt is required for IL-17A production, and RORγt deficiency protects against cisplatin-induced nephrotoxicity (92). IL-17A induces neutrophil migration through CXCL5, a chemokine known to be associated with higher risk of renal damage. Interestingly, high IL-17C expression has been noted in kidney epithelial cells following fungal infection (6), whereas lack of IL-17C in mice was associated with lower renal damage and improved survival (78). Altogether, the evidence supports that IL-17-induced responses potentiate AKI in septic patients.

Gut Barrier Dysfunction
Intestinal mucosa dysfunction remains a challenge in the management of sepsis (64). Sepsis-induced gut barrier dysfunction includes disrupted mucosal integrity, increased permeability of the epithelial lining, impairment of gut-blood barrier, and bacterial translocation (90).
IL-17A is important in maintaining the integrity of epithelial barriers (8). IL-17A-mediated pathological responses disrupt intestinal epithelial barrier function, increase gut permeability, and cause translocation of gut bacteria by inhibiting proliferation of enterocytes and inducing their apoptosis (8,9). Disseminated gram-positive bacteria can upregulate IL-17A by activating Toll-like receptor (TLR)-2 on T cells and dendritic cells (47). Neutralizing IL-17 in septic mouse models protects gut barrier integrity, reduces systemic inflammation and bacterial dissemination, and lowers mortality (41).

Cardiomyocyte Dysfunction
Cardiomyocyte dysfunction is a complication that contributes to high mortality in sepsis patients (90). The molecular mechanisms underlying sepsis-induced cardiomyopathy are not well defined, but may involve a combination of endothelial disturbance, autonomic nervous system alterations, dysfunction of calcium regulation, oxidative and mitochondrial stress, extensive inflammation, and myocardial ischemia and reperfusion (I/R) injury (90). Up to now, no efficient treatment for sepsis-induced cardiomyopathy exists.
IL-17A levels are greatly increased in post-myocardial I/R injury, inflammation, and apoptotic responses (94). IL-17A accelerates the release of chemokines and proinflammatory mediators from fibroblasts, endothelial cells, leukocytes, and neutrophils (95). In viral myocarditis, neutralizing IL-17A with a monoclonal antibody attenuates myocardium inflammation, clinical symptoms, and disease progression (96). Knockdown of IL-17A in mice greatly mitigates cardiac disturbance as well as myocardial I/R injury and remodeling (97). Anti-IL-17A antibodies downregulate CCL3, CXCL1, and IL-6 in cardiomyocytes of mice with sepsis induced by CLP, suggesting that IL-17A contributes to sepsis-induced cardiomyopathy (96). Interestingly, high mobility group box-1 protein (HMGB1), a crucial late biomarker of lethal systemic inflammation in sepsis, stimulates IL-17A release during myocardial I/R injury (98). Conversely, HMGB1 inhibition remarkably lowers IL-17A levels and attenuates myocardial I/R injury (98). Therefore, the HMGB1/IL-17A axis may play a key role in myocardial dysfunction resulted from sepsis.

Other Sepsis-Related Complications
Hepatic dysfunction is a prominent feature of sepsis with crucial implications for survival, since it contributes to sepsis-induced multiple organ failure (89). IL-17 from γδ T cells protects the host from Listeria monocytogenes infection by augmenting bacterial clearance through the liver (67). Absence of IL-17A or γδ T cells in mice is associated with greater bacterial load and inflammatory lesions in the liver (67). However, another study showed that IL-22, but not IL-17A, could protect hepatocytes from acute liver inflammation (99). The precise role of IL-17 in sepsis-induced hepatic damage remains unclear and requires deeper investigation.
The stress response following sepsis involves production of glucocorticoids and catecholamines (90). Both glucocorticoids Frontiers in Immunology | www.frontiersin.org and catecholamines inhibit the expression and production of IL-17A in lipopolysaccharide-stimulated peritoneal macrophages (90). They also block c-Jun-N-terminal kinase, preventing IL-17A secretion (42). Taken together, excessive IL-17A production disrupts immune homeostasis and contributes to the development and progression of sepsis. Nevertheless, the exact contribution of IL-17 to sepsisinduced dysfunction of the liver and other organs needs to be further explored.

Administration of Exogenous IL-17 or Targeting IL-17 in Sepsis
IL-17A is an important link between the innate and adaptive immune processes (43,49). IL-17A-deficient mice are more susceptible to sepsis than wild-type controls (37), and IL-17A blockade impairs peritoneal eradication of E. coli, indicating that IL-17A might prevent sepsis in certain settings (63). Consistent with this idea, IL-17A administration restores impaired immunity in CXCL1-knockout mice (44). In animals infected with K. pneumoniae, treatment with IL-17A promoted bacterial clearance and neutrophil recruitment by enhancing the production of G-CSF, IL-1β, TNF-α, and CXCL-2 (36). Likewise, IL-17A administration improved anti-bacterial immunity following challenge with group B Streptococcus and Streptococcus pneumoniae in mice (34). Neutralization of IL-17A promoted resistance to intra-abdominal abscess formation in mice challenged with Bacteroides fragilis or abscess-inducing zwitterionic polysaccharides (35). Neutralizing IL-17A with antibodies could also reduce the mortality of mice immunized with S. aureus iron regulated surface determinant B after bacterial challenge (40). Thus, IL-17A plays a pivotal role in prevention of infection progression and related infectious complications.
In agreement with the findings described above, inhibition of IL-17/IL-23 significantly improved survival (from 40 to 100%) in a mouse model of endotoxic shock (39). Likely, anti-IL-17A antibody reduces systemic levels of proinflammatory cytokines/chemokines and bacteremia, improving the survival rate (50). E. coli infection results in high levels of IL-17, and blockade of IL-17 attenuates neutrophil infiltration and improves bacterial clearance (63).
In a recent study, anti-IL-17 antibody mitigated the pathology and the mortality rate of mice infected with Pseudomonas aeruginosa (100). In a colitis mouse model, IL-17 neutralization attenuated immunopathology and bacteremia (5). In a neonatal sepsis mice model, treatment with IL-17A-neutralizing antibody mitigated IL-18-related disease deterioration (57). Targeting IL-17A enhanced IL-10 production in peripheral blood mononuclear cells following sepsis (57). This evidence supports the possibility of reducing sepsis mortality through antibodymediated blockade of IL-17R or IL-17A ( Table 2). Anti-IL-17A antibodies ixekizumab and secukinumab are currently being investigated in clinical trials in septic patients (8,9).

SUMMARY AND PERSPECTIVES
IL-17A can regulate host defenses against invading pathogens by producing chemokines, AMPs, and proinflammatory cytokines. In this way, IL-17A forms part of the alarm signal by sentry-like immune cells to stimulate host defenses. On one hand, IL-17A interacts with various mediators (e.g., TNF-α, IL-1, IL-6) to induce tissue-infiltrating neutrophils to eliminate the invading pathogens. On the other hand, IL-17A may interact with other proinflammatory cytokines to drive exaggerated immune response, and contribute to the development of inflammatory and autoimmune diseases. There is burgeoning evidence that IL-17A participates in the pathophysiology of sepsis, with respect to regulation of inflammatory and immune responses. Consistently, elevated level of IL-17A is apparently related with disease severity in sepsis, suggesting a potential biomarker of prognosis in the clinical setting.
Moreover, developing IL-17A as a therapeutic target must consider the fact that IL-17A might be either protective or pathogenic, depending on the specific circumstances. Future work will be needed to deeply explore the pathophysiological mechanisms by IL-17A interfere with divergent immune responses during sepsis. In addition, studies are warranted to evaluate the other forms (IL-17B-IL-17F) in clinical settings.

AUTHOR CONTRIBUTIONS
YY conceptualized the study. YG and MH conducted the literature review and drafted the manuscript. All authors contributed to the article and approved the submitted version.