Immunity and Fibrogenesis: The Role of Th17/IL-17 Axis in HBV and HCV-induced Chronic Hepatitis and Progression to Cirrhosis

Cirrhosis is a common final pathway for most chronic liver diseases; representing an increasing burden worldwide and is associated with increased morbidity and mortality. Current evidence has shown that, after an initial injury, the immune response has a significant participation in the ongoing damage, and progression from chronic viral hepatitis (CVH) to cirrhosis, driving the activation and maintenance of main fibrogenic pathways. Among immune deregulations, those related to the subtype 17 of T helper lymphocytes (Th17)/interleukin-17 (IL-17) axis have been recognized as key immunopathological and prognostic elements in patients with CVH. The Th17/IL-17 axis has been found involved in several points of fibrogenesis chain from the activation of stellate cells, increased expression of profibrotic factors as TGF-β, promotion of the myofibroblastic or epithelial–mesenchymal transition, stimulation of the synthesis of collagen, and induction of imbalance between matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). It also promotes the recruitment of inflammatory cells and increases the expression of proinflammatory cytokines such as IL-6 and IL-23. So, the Th17/IL-17 axis is simultaneously the fuel and the flame of a sustained proinflammatory and profibrotic environment. This work aims to present the immunopathologic and prognostic role of the Th17/IL-17 axis and related pathways in fibrogenesis and progression to cirrhosis in patients with liver disease due to hepatitis B virus (HBV) and hepatitis C virus (HCV).


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The Role of Th17/IL-17 Axis in Hepatic Fibrogenesis Frontiers in Immunology | www.frontiersin.org September 2017 | Volume 8 | Article 1195 of CVH during the last decades, the number of deaths from cirrhosis and hepatocellular carcinoma (HCC) increased in the last 20 years (2,3). Currently, it is known that after the initial injury, before cirrhosis is established, multiple pathways of fibrogenesis are activated as a result of continuous interaction between pathogenrelated factors (4)(5)(6), the host genetic such as certain HLA haplotypes and cytokines gene polymorphisms (7)(8)(9)(10)(11), liver resident cells, and the immune system (9)(10)(11)(12)(13) (Figure 1). Indeed, cirrhosis is a reflection of sustained injuries and constant and exaggerated attempts of tissue repair, in which the immune system has crucial participation (14)(15)(16). The inappropriate immune response have an influence on the activation and maintenance of fibrogenic pathways and progression from CVH to cirrhosis (17)(18)(19)(20). Multiple imbalances in immune response, either in cellular or soluble factors, have been associated with the evolution to cirrhosis in viral hepatitis (21,22). In addition, the immune response influences on viral persistence and response to treatment (11,23). Thus, efforts have been made in research and clinical practice, aiming to get a better comprehension of the immunological mechanisms underlying these pathways, their exploration as immune biomarkers to predict outcomes, response to treatment, as well as explore their potential as targets for adjuvant therapeutics (24)(25)(26).
Among the elements of the immune response, the subtype 17 of T helper lymphocytes (Th17) has gained space as a biomarker with noteworthy performance in the prediction of progression to cirrhosis in liver diseases, particularly in CVH (20,28). Therefore, the cytokines secreted by Th17, particularly the interleukin-17 (IL-17), also have been implicated in the activation of fibrogenic pathways and progression to cirrhosis (13,17). Th17 cells have a predominantly effector functional profile, being responsible for the immune surveillance, but are also involved in the pathogenesis of many autoimmune diseases and in the mechanisms of fibrosis in many organs, after the initial injury (29)(30)(31).
In CVH, the Th17/IL-17 axis expresses a sustained aggression, and especially a proinflammatory and profibrotic environment with recruitment and activation of other cells, promoting this way, more tissue injury and dysfunctional reparative responses (13,17,32,33). This review aims to summarize the existing knowledge on the immunopathologic and prognostic role of the Th17/IL-17 axis and related pathways in fibrogenesis and progression to cirrhosis in patients with liver disease due to hepatitis B virus (HBV) and hepatitis C virus (HCV).

AN OveRview OF GeNeRAL iNFLAMMATORY BiOMARKeRS AS OUTCOMe PReDiCTORS iN CvH
General Inflammatory biomarkers, such as C-reactive protein (CRP), and interleukin-6, have been associated with poor outcomes on viral hepatitis (11,26,34). High levels of interleukin-6 are related to adverse outcomes in the CVH, including greater severity (35,36), worse response to treatment and viral persistence (11,26), and evolution to cirrhosis, HCC, or death (35,36). In a study including 149 patients with CHC (and 17 controls) who underwent 12 weeks' treatment with pegylated IFN-α2b and ribavirin, serum IL-6 levels were significantly higher in CHC patients than in controls, and a high pretreatment IL-6 was associated with lower rates of sustained virologic response (SVR) (52 vs. 79%; P = 0.012) (26). In addition, SVR was accompanied by a significant decrease in IL-6 levels (from 2.7 to 1.5 pg/ml; P = 0.029) at 4 weeks of treatment, remaining significantly lower in responder than in non-responder (26). In other studies, it was observed that certain polymorphisms in IL-6 or its promoter are associated with lower rate of spontaneous clearance (11), and increased risk of HCC in patients with CVH-related cirrhosis (10,37). Many other proinflammatory cytokines, including interleukin IL-1β, IL-18, and TNF-α have been associated with increased risk of progression to cirrhosis (38-40). Certain polymorphisms in TNF-α are also associated with higher risk of becoming chronic carriers of viral infection, progression to cirrhosis and HCC (15,40).
In addition to the soluble factors, cells of the inflammatory response as neutrophils (19,41) and monocytes have been found associated with worse outcomes in viral hepatitis. All these elements (cells and soluble factors) are part of a context in which the Th17/IL-17 axis imbalances work as crucial elements to feed and keep this proinflammatory and profibrotic microenvironment (20,22,(42)(43)(44), as described in the next sections.

THe TH17/iL-17 AXiS AND OUTCOMe PReDiCTiON iN CvH
The inappropriate immune response at the level of the Th17/IL-17 axis exerts influence in maintaining the fibrogenic pathways and progression from CVH to cirrhosis (9,44). The fibrogenic role of IL-17, the main cytokine of Th17, has been appointed in increasing number of publications in recent years (13,45,46). In addition to its direct effect on fibrogenesis, the Th17/IL-17 axis is the fuel to sustain the proinflammatory environment, with the recruitment of the other cells and stimulation of the synthesis of other soluble factors (29,33,(47)(48)(49)(50). At the same time, Th17/IL-17 axis expresses itself, a response to a sustained proinflammatory stimulus (51, 52). So, we can understand the broad scope of the elements of this axis on the CVH, predicting outcomes in different points of the disease, from spontaneous healing (53), response to treatment (23,54,55), occurrence of acute decompensations (56), progression to cirrhosis (9,28), and HCC (53), including post-transplant recurrence (57), as detailed in this section.

The Th17/iL-17 Axis and Severity of CvH
The Th17/IL-17 axis is associated with high disease severity in CVHs, as found in a study where patients with chronic hepatitis B (CHB) had higher percentage of Th17 cells in peripheral blood than healthy controls (HCs) (1.53 vs. 0.92%); and among patients there was a positive correlation between peripheral Th17 cells and serum alanine aminotransferase (ALT) (58). In another study, including 96 patients with HBV-related conditions, the serum IL-17 concentration, intrahepatic, and peripheral Th17 cells were significantly higher in both CHB and acute-on-chronic liver failure (ACLF) patients than in asymptomatic surface antigen carriers (AsC) or HCs (59). Th17 cells increased progressively as aggravated the immune inflammation from AsC, CHB, to ACLF, with a positive correlation with severity markers (INR and MELD score) (59). Compared with HCs, patients with CHC had also higher proportions of Th17 cells either circulating (1.56 vs. 0.96%) or infiltrating the liver (16.08 vs. 0.82/hpf), associated with higher serum IL-17 levels (84.86 vs. 60.52 pg/mL) (42). In these patients, both peripheral and intrahepatic Th17 cells correlated with the severity of liver inflammation and damage (28,42).

The Th17/iL-17 Axis and Progression to Cirrhosis in CvH
Concerning the progression to cirrhosis, in a study including 173 patients with chronic liver diseases, there was a significant increase in serum IL-17 protein and IL -17 mRNA levels in chronic HBV-related conditions than in HCs (P < 0.001); and patients with cirrhosis exhibited the highest serum IL-17 and IL-17 mRNA in peripheral blood mononuclear cells (PBMCs) (44). In another study with 101 patients with HBV-related LC or CHB; peripheral Th17 cells increased significantly in patients with cirrhosis as increased disease severity (mean: 3.51, 3.94, and 4.46; for Child-Pugh A, B, and C, respectively) (28). In intrahepatic tissue, a study conducted among 91 patients with chronic liver diseases, there was a significant increase intrahepatic expression of IL-17 in chronic HBV-related conditions than in HCs; furthermore, intrahepatic IL-17 was mainly localized in the fibrosis region, and its level correlated strongly with the degree of fibrosis (60). Other studies have also found increased intrahepatic IL-17+ cells or IL-17 levels, which correlate positively with fibrotic staging scores and clinical progression from CHB to cirrhosis, and most IL-17+ cells located in the fibrotic area (28,44). In addition, intrahepatic IL-17 accompanied the higher serum IL-17 protein and mRNA levels in PBMCs, being higher among patients with cirrhosis than those with CHB, or HBsAg carriers (P < 0.01, for both) (44). Among HCV patients, a study evaluating the effect of HCV recurrence after orthotopic liver transplantation (OLT) showed that recipients with significant HCV-induced allograft fibrosis/cirrhosis and inflammation, presented higher frequency of HCV-specific Th17 cells, as well as proinflammatory mediators (IL-17, IL-1β, IL-6, IL-8, and MCP-1) (57).
In genetic studies, it has been noted that certain polymorphisms in IL-17 genes are more often present among those who progress to LC than in CHB patients (9,14,53); and are associated with a significant increase in LC risk either among monozygotic patients [OR 4.1, 95% CI: 1.4-11.84 or single allele carriers (OR 1.8, 95% CI: 1.16-2.9)] (14).

The Th17/iL-17 Axis and the Response to Treatment in CvH
In CVH, the Th17/IL-17 axis status is associated with response to available treatments (23), as found in a study with 30 CHB patients, in which treatment with entecavir was associated with a significant decrease in the Th17 and Treg cell frequencies and related cytokines, in parallel to the reduction of HBV DNA load (61,62). In other studies in CHB, the treatment either with telbivudine or with interferon-α resulted in the normalization of serum ALT and reduction or suppression of viral replication, associated with a significant decline in circulating Th17 cells and IL-17 levels (23,54). Studies in HCV also found the same effect, as shown in a study including 27 HCV-infected patients, in which combined treatment with pegylated IFN-α and ribavirin resulted in a significant decrease in factors related to Th17 (IL-6 and IL-17), Th1 (IFN-α and MIP-1) responses, and profibrotic factors (FGFb, VEGF); and this impact was principally in responder patients (62). In another study, Th17-related gene polymorphisms were associated with sustained responses to PEG-IFNa-2α (55).
In line with these findings, in an interventional study involving 56 cirrhotic patients allocated to autologous bone marrow mesenchymal stem cells (ABMSCs) transplantation or control group; transplantation significantly improved the liver function, accompanied by a marked decrease in Th17 cells and serum levels of proinflammatory cytokines (IL-17, TNF-α, and IL-6) (63).

The Th17/iL-17 Axis and Mortality Prediction in CvH
Beyond its effect in predicting disease severity, the Th17/IL-17 axis elements are also predictors of mortality (56). In a study including 60 HBV-infected patients (30 with CHB and 30 with ACLF), the disproportionate increase of Th17 (compared to Treg) was associated with low survival among those with ACLF (64). These results have also been found in another study including 98 patients with HBV-related conditions (70 with CHB and 28 with LC), where the low Treg/Th17 ratio was associated with low survival among patients with cirrhosis and was associated with worse Child-Pugh and MELD scores (65). In another study, including 80 HBV-infected patients (40 with ACLF and 40 with CHB), the frequency of Th17 cells in peripheral blood, as well as IL-17 mRNA level in PBMCs, was significantly higher among ACLF patients who died than among survivors; and correlated positively with serum total bilirubin (r = 0.392, P = 0.012) and MELD score (r = 0.383, P = 0.015) (56). These findings suggest a significant contribution of this immune imbalance in disease severity and mortality.

The Role of Other iL-17 Sources and Related imbalances in CvH Outcomes
Besides the Th17 cells, recent investigations have found other immune cells, such as mast cells, and neutrophils as important sources of IL-17 in CVH, especially in late fibrosis stages (66)(67)(68). These findings emerge in a context after many studies have shown the domain of neutrophils as a predictor of outcomes in viral hepatitis and related diseases (19,41). Therefore, these research together bring to light the importance of the interleukin-17 in pathogenesis and progression of CVH and can be one of the ways by which neutrophils, and other immune cell populations, exercise their pathogenic and predictive effect in CVH. Other Th17-related cytokines, such as IL-6 and IL-23, are involved in the evolution of CVH, regardless of stimulation of Th17 (11,37,69). The IL-23 and its receptor, in particular, have been found higher among HCV-infected patients than in control (mean 24.6 vs. 20.2 pg/mL; P = 0.005), with a positive correlation with ALT in HCV patients (69). Concerning the IL-6, its role was described in previous sections. Besides increased Th17 cells, CVH has been associated with decreased or disproportionate count of regulatory T lymphocytes (Treg), another T helper subset, which is the functional counterbalance of Th17 cells (70); configuring a Treg/Th17 imbalance (13,42,64,71). The balance between these two T helper lymphocytes subpopulations is fundamental (21,22), and influenced by various factors (72)(73)(74). There is a plasticity and reciprocity between the two cell subpopulations that depends on environmental factors (70,75,76), being the proinflammatory environment, like that of the CVH, favorable to the polarization to Th17 cells (77,78). The Treg/Th17 imbalance has been associated with greater hepatocellular damage in CVHs (21,71,79) and is related to advanced stages of cirrhosis and HCC (22,65,79), correlating inversely with severity scores and mortality (22,64,65). The Treg/Th17 imbalance has also been observed in other fibrosing liver diseases, such as autoimmune liver diseases (ALD) (80), biliary atresia (81), primary biliary cirrhosis (PBC) (82-84), non-alcoholic steatohepatitis (85,86), schistosoma-induced hepatitis (87)(88)(89), and drug-induced hepatitis (90,91). Table 1 summarizes the clinical studies that evaluated the role of the Th17/IL-17 axis and related imbalances as drivers and predictors of outcomes in CVH.

MeCHANiSMS AND PATHwAYS LiNKiNG THe TH17/iL-17 AXiS TO FiBROGeNeSiS AND CiRRHOSiS iN CvH
The Th17 Differentiation and Th17-Secreted Cytokines Overall, Th17 cells differentiate from naive T helper cells, in response to a variety of stimuli, in the presence of key cytokines, namely IL-1β, IL-6, IL-21, IL-23, and TGF-β (101)(102)(103)(104)(105). In viral hepatitis, the virus particles are recognized by toll-like receptor (TLR2 and TLR4) present on the surface of the antigen-presenting cells (dendritic cells, macrophages, and monocytes) that result in their activation (97,106). These activated cells, using the nuclear factor kappa B (NF-κB) and/or mitogen-activated protein kinase (MAPK) signaling pathways, produce the proinflammatory cytokines IL-1, IL-6, IL-21, and IL-23 (38, 93, 107) that drives the Th17 differentiation (93,104,107,108). In the particular case of HCV, there are two additional pathways: the first one consists in the production of the thymic stromal lymphopoietin (TSLP) by HCV-infected hepatocytes, in an NF-κB-dependent process, and is this hepatocyte-derived TSLP that enhances activated APCs to produce the IL-1, IL-6, IL-21, and IL-23 (109). The second consists in particular evidence that HCV core protein exerts a function of a toll-like receptor 2 ligand, promoting, by itself, the activation of the APCs, the production of inflammatory cytokines that favor Th17 differentiation, and the evasion of the immune system (4,12,27). After being differentiated, the Th17 cells secrete its cytokines (IL-17, IL-21, and IL-22), being the IL-17 the main driver of a chain of events that have in common the favoritism of the proinflammatory and profibrotic pathways (13,47,49).
In the liver, Th17 cells produce their cytokines (93), with IL-17 being the most associated with the progression of cirrhosis (13,28,49). There are receptors for IL-17 expressed in hepatocytes, in the liver sinusoids endothelial cells, in hepatic stellate cells (HSCs), and Kupffer cells (KC) (13). The functional implication of IL-17 in liver tissue is well characterized in the activation and/or stimulation of HSCs and KC (13,17,127) and cholangiocytes (115,116). The frequency of liver IL-17+ T cells was significantly higher in both HBV-related liver failure (CLF and ACLF) than in HC (P = 0.0001). The IL-17+/Treg ratio was significantly higher in ACLF and CLF than in HC (7.00, 4.33, and 0.00, respectively). The IL17+ T cells frequency correlated positively with total bilirubin (r = 0.579, P = 0.001) and MELD score (r = 0.367, P = 0.043)  The frequency of circulating Th17 cells was significantly increased in liver allograft recipients who developed acute rejection; whereas Tregs, and consequently the Tregs/Th17 ratio, was significantly decreased in these patients. The level of Th17 cells had a positive correlation with RAI (r = 0.890, P < 0.001).   induces the rapid translocation of transcription factors NF-κB and Stat3 to the cellular nucleus (13), where activate the gene transcription of proinflammatory cytokines (IL-6 and TNF-α) and profibrotic factors (TGF-β1) (17,50). In addition, IL-17 promotes the proliferation of HSCs, the upregulation of TGF-β receptor, IL-17RA, and IL-17RC (13,16,127). So, the IL-17 has the property to induce the activation of HSCs and fibrogenesis, and this effect seems to be synergistic with that of IL-6 and TNF-α (13,128).
In the liver tissue, particularly in HSCs, the IL-17 also presents the following effects: increases the genic expression of type I collagen and induces its production through TGF-β, or Stat3/SMAD2/3 signaling pathways (13,127). In addition, IL-17 upregulates matrix metalloproteinases (MMP2, MMP3, and MMP9) expression via NF-κB and Stat3 signaling pathways (13,127,129) and increases the expression of tissue inhibitor of matrix metalloproteinase I (TIMP1) and the production of related proteins (127). The combination of these effects results in increased production of extracellular matrix and changes in its degradation. This role of IL-17 has been reinforced in experimental model where liver fibrosis was inhibited or attenuated in IL-17RA−/− mice exposed to carbon tetrachloride (CCl4) or subjected to bile duct ligation (BDL), associated with reduced mRNA expression of fibrogenic genes (collagen-α1, MMP3, TIMP1, and TGF-β1) (13,130). The role of IL-17 on MMPs and related signaling pathway has also been found in other organs such as the heart (131).

IL-17, TGF-β, and Induction of Cellular Transition/Transdifferentiation
In addition to the direct effects, described above, the IL-17 cooperates with TGF-β1 to induce the activation of HSCs and their transition into a proliferative, contractile, and fibrogenic phenotype-the myofibroblast (13,132,133). These events also lead to an excessive synthesis of ECM and the contractility of myofibroblasts resulting in changes in the hepatic microarchitecture and microcirculation (134)(135)(136). The IL-17 also has the effect of inducing epithelial-mesenchymal transition (EMT) in hepatic tissue as observed in hepatocytes of patients with HCC (137) and biliary epithelial cells as seen in PBC (115). It is important to emphasize that the exposure of the hepatic tissue to IL-17 increased the expression of TGF-β in almost all liver resident cells (13,127). Moreover, the TGF-β is well documented that induces the EMT of the hepatocytes (138)(139)(140). Therefore, we can deduce that the IL-17, through the induction of TGF-β production, is an indirect promoter of EMT in the liver (13,132,137,139). This effect of IL-17 in EMT is well described in many other organs (and clinical conditions), as in the respiratory epithelium (141,142) and prostate (143); and has been proven to be a process dependent on TGF-β or NF-κB pathways (115,141,142,144).
The activation of HSCs is associated with two other Th17/ IL-17 axis-related changes. The first results from the rarefaction of retinoic acid in HSCs. Under normal conditions, the quiescent HSCs have many granules containing retinoic acid (135), which acts inhibiting the Th17 and favoring the Treg cells differentiation, with a protective effect on the liver (145,146). However, when activated HSCs undergo changes in their metabolism and retinoic acid content, which affects the differentiation of Treg cells and, consequently, the loss of the protective effect (135,147,148). The second results from the evidence that activated HSCs exacerbate liver fibrosis by enhancing IL-17A production by T cells, in a TLR3-dependent manner (45), that in combination with the rarefaction of retinoic acid results promoting further Treg/Th17 imbalance and fibrogenesis (45, 149).

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The Role of

The Role of iL-17 in the Systemic Circulation and its Repercussions in the Liver Tissue
In the systemic circulation, the IL-17 sustains the proinflammatory environment, stimulating the granulopoiesis through the release of granulocyte-macrophage colony-stimulating factor (GM-CSF) (33,(155)(156)(157)(158). On inflammatory cells (either in systemic circulation or infiltrating the liver), the IL-17 induces the release of the IL-6 (159). The elevation of the IL-6 contributes to further Th17 responses because it promotes its differentiation (104), as IL-6 receptors are expressed on the surface of CD4+ T cells (43, 51). This process also occurs using the STAT3, NF-κB, and MAPK signaling (43,151). The repercussion at the organic level is the liver infiltration by inflammatory cells that occurs because IL-17 promotes endothelial activation (32,33,47), and release of attracting chemokines such as CXCL5 and CXCL8/IL-8 (156,160,161) whose receptors (CXCR1 and CXCR2) are abundantly expressed neutrophils and monocytes (32,125,(161)(162)(163)(164). Once in the liver, neutrophils are involved in various points of the fibrogenesis chain, including the release MMP9 (165)(166)(167) and seem to affect the functioning of the TIMP-1 (168). Recent studies have shown that neutrophils released itself the IL-17, mainly in the advanced stages of fibrosis (66); and there is a sustained cross talk between neutrophils and Th17 cells (32,164). Figure 2 represents the chain of events from viral injury, Th17/IL-17 axis activation, to liver fibrogenesis and cirrhosis.

The Role of iL-17 Axis in Other Liver Diseases and Other Organs Fibrosis
The role of Th17/IL-17 axis in hepatic fibrosis has been found in various liver diseases such as NASH (117,118), obstructive cholestasis (169), PSC (112), PBC (16,114,115), biliary atresia (29,116), drug-induced (91,170), protozoaassociated cirrhosis (87,171,172), and viral hepatitis (20,30,44,173). Moreover, the role of Th17/IL-17 axis extends to related diseases such as HCC (94,174,175), which suggests a continuous, or at least related parts of a whole, in the pathogenesis of these conditions (53, 94,174,175). Additional evidence comes from observational studies that have found an increased occurrence of hepatic inflammation associated with dysregulated protein/lipid metabolism, and progression to cirrhosis in clinical conditions such as psoriasis that have the Th17/IL-17 axis hyperactivation as the crucial point in their pathogenesis (48,176). It is worth noting that HCV infection induces the development of autoantibodies to liver autoantigens, in up to 10% of patients, in addition to previously described mechanisms, leading to an overlap between CVH and AIH (177)(178)(179)(180). Certainly, the Th17/IL-17 axis plays a pivotal role in the progression to cirrhosis regardless of the dominant mechanism in the pathogenesis (20,49,111,181,182).
The role of the Th17/IL-17 axis has been found in other diseases with a fibrosing behavior in various organs such as intestine (31,183), lung (184,185), and peritoneum or kidney (46, 186); and its block has shown to prevent/mitigate the fibrosis in many pathological conditions (187)(188)(189).
Hepatoprotective Agents Targeting the Th17/iL-17 Axis, Associated Cytokines, and Signaling Pathways As we have seen the Th7/IL-17 axis is involved in several known points of fibrogenesis chain, including the activation of HSCs (17), recruitment of inflammatory cells (32,160), expression of proinflammatory and profibrotic cytokines (127), in stimulus to collagen synthesis, and in the imbalance between MMP and TIMPs (13,127,133). Added to this is the parallel evidence of being a promoter of EMT or myofibroblast transition (115,137,142). Therefore, the inhibition of Th17/IL-17 axis (and its signaling pathways) represents a promising strategy in the treatment of organic fibrosis.
Agents That Downregulate the Th17/IL-17 Axis or Restore the Treg/Th17 Balance There are a variety of agents targeting these immune pathways, with the potential to slow down the CVH-induced cirrhosis. From those that downregulates the Th17/IL-17 axis to those that restore the Treg/Th17 balance. Brief citations are made about some of these agents that have shown benefit in preliminary studies, such as cannabinoid receptor 2 agonists, whose action is to counteract immune and fibrogenic responses induced by interleukin-17 (190). Another treatment that ameliorates hepatic fibrosis by regulation of Treg/Th17 cells, and downregulating the IL-17, is bone marrow-derived stem cells transplantation (63,191). It is also worth to cite the vitamin D and analogs that inhibit the development of liver fibrosis by reducing the Th17 differentiation and IL-17 production, and activate the Treg differentiation (186,(192)(193)(194). The rapamycin demonstrated to improve hepatic fibrosis that was associated with a decrease of Th17 and expansion of Treg (91,195). In another study, the administration of an mTOR inhibitor decreased the IL-17 production induced by IL-6; and this effect occurred through decreasing mTOR/STAT3 activation (43). Halofuginone, an inhibitor of Th17 cells differentiation (196); has shown to be a promising antifibrotic drug, and its impact in reducing liver fibrosis severity is associated with a significant reduction in Th17 cells and related cytokines (197). Another compound with protective effects in liver fibrosis is the polyphenolic molecule mongol that inhibits Th17 cells differentiation and suppresses HSCs activation (198).
Still, about Treg/Th17 balance restoration, adoptive transfer of Tregs ameliorated the severity of liver injury, accompanied by increased levels of hepatic Treg and IL-10 as shown in a model of Triptolide-induced liver injury (90). On the other hand, some drugs with use and efficiency established in viral hepatitis, such as interferon, appear to have effects that involve this axis, among its various mechanisms (24,62,187).

Agents Targeting the Receptors and Signaling Pathways Involved in Th17/IL-17 Axis Effects
The inhibition of the activation of HSCs is, undoubtedly, one of the most attractive strategies to slow down fibrogenesis (199). Multiple receptors and signaling pathways are involved in the chain of events of Th17/IL-17 axis-mediated HSCs activation, and can also be therapeutic targets. So, agents such as resveratrol, curcumin, Dioscin, the flavonoid quercetin, and other agents have emerged as inhibitors of the HSCs activation targeting the TLR3, TLR2/4, STAT3, and/or MAPK/NF-κB, the main receptors and pathways in Th17/IL-17 axis-mediated HSCs activation (200)(201)(202)(203)(204)(205)(206)(207). Agents such as rosiglitazone and rapamycin demonstrated the potential to interfere with the fibrogenic pathways by reducing the expression of TGF-β (195,208). Others such as the ruxolitinib have also shown the potential to inhibit the hepatotoxicity and fibrogenesis, after initial injury by multiple agents, by inhibiting the JAK/STAT pathway (207,209,210).

CONCLUSiON AND FUTURe DiReCTiONS
The imbalanced immunity at Th17/IL-17 axis level plays a significant role in liver fibrogenesis after initial HCV or HBV injury. The Th17/IL-17 axis drives of a chain of events that promote a proinflammatory and profibrotic environment by recruiting neutrophils and monocytes and by inducing the expression and production of interleukin-23 and IL-6 either in the liver or peripheral cells. All resident liver cells express receptors for IL-17; and liver cells respond to the IL-17 exposition by increasing the expression of profibrotic and proinflammatory factors such as TGF-β, MMPs, and TIMP. In addition, IL-17 induces the transformation of HSCs to myofibroblasts and the EMT of the hepatocytes, promoting the synthesis of extracellular matrix, cell contractility, and all changes in the liver microstructure and microcirculation.