Interleukin (IL)-17 (IL-17A) is a member of the Th17 family of cytokines comprised of IL-17A, IL-17F, IL-17B, IL-17C, and IL-17E. IL-17 signaling plays a critical role in mediating autoimmunity, such as the autoimmune inflammatory diseases psoriasis and rheumatoid arthritis that respond to anti-IL-17 biological therapies. More recently, IL-17 has been implicated in liver, lung, and skin fibrosis, and in tumorigenesis. Mainly produced by CD4+ Th17 cells,[3-5] IL-17 mediates its biological function by way of signaling through a complex of IL-17RA and IL-17RC receptors. IL-17RA is ubiquitously expressed, but is rapidly and highly induced in hematopoietic cells and fibroblasts. IL-17 stimulates Kupffer cells/macrophages to express inflammatory cytokines IL-6, IL-1β, and tumor necrosis factor alpha (TNF-α) and profibrogenic transforming growth factor beta1 (TGF-β1) to directly induce activation of myofibroblasts. Further, deletion of IL-17RA in mice protects from liver fibrosis induced by cholestatic or toxic liver injury.
There is a growing body of evidence that the IL-17 signaling pathway contributes to the pathogenesis of liver diseases of many etiologies. The featured article by Harley at al. demonstrates that IL-17 signaling promotes the progression of nonalcoholic fatty liver disease (NAFLD): specific emphasis is placed on progression of nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). NAFLD, which has become the leading cause of liver disease in developed countries, is largely associated with obesity and metabolic syndrome. About 20% of patients with NAFLD develop NASH, a condition characterized by hepatic injury and inflammation, which may lead to advanced fibrosis, cirrhosis, and hepatocellular cancer. Although significant progress has been made in understanding the pathogenesis of NAFLD, multiple aspects of the complex interaction between genetic factors, metabolic dysregulation, the liver-brain axis, and the gut microbiome are not fully understood.
Although IL-17 signaling is implicated in maintenance of a lean phenotype,[12-14] obesity is associated with expansion and accumulation of proinflammatory Th17 cells in adipose and liver tissues. Harley at al. demonstrate a regulatory role of IL-17 signaling in the progression of NASH. Using two models of NAFLD in mice, the authors demonstrate that obesity-induced hepatocellular injury requires IL-17 signaling. Consistently, high-fat diet (HFD)- or high-fat high-carbohydrate diet (HFHCD)-fed IL-17RA knockout mice become obese and significantly increase hepatic triglyceride deposition. However, despite increased steatosis, these mice are protected from glucose dysmetabolism, suggesting that steatosis alone does not facilitate NAFL progression to NASH. Thus, despite the fact that steatosis may sensitize hepatocytes to hepatocellular damage, IL-17RA-driven recruitment of neturophillic/myeloid cells inflammatory immune infiltrate and induction of reactive oxygen species (ROS) production appears to be critical for progression of NAFL to NASH.
Obesity-mediated intestinal microbiota facilitates Th17 cell expansion and IL-17 secretion. In obese humans, the predominant gut bacteria are the Firmicutes, which are capable of breaking down hard-to-digest dietary polysaccharides, leading to their absorption and subsequent weight gain. Notably, transfer of gut microbiota from obese to lean mice induces rapid weight gain, further suggesting that gut microflora play a role in the development of obesity.[18, 19] Intestinal microbiota are also shown to play a critical role in absorption of lipopolysaccharide (LPS). Segmented filamentous bacteria (SFB) or Candidatus Arthromitus, characterized over three decades ago, uniquely attach to the apical epithelium of small intestine. Mono-colonization of mice with SFB leads to immunological changes in mice, particularly within the small intestine. SFBs play a critical role in the induction of proinflammatory factors, and can be accounted for expansion of Th17 cells to produce IL-17 and IL-22. Consistently, Harley at al. demonstrate that colonization of mice with SFB augments IL-17 production in wild-type mice or leptin receptor-deficient (db/db) mice. Therefore, it is likely that colonization of mice with SFB may further facilitate systemic inflammation in mice. In fact, Harley et al. have shown that colonization of mice with SFB exacerbates hepatocellular damage in the context of obesity, while SFB depletion is protective.
Taken together, Harley at al. have linked metabolic dysregulation, the IL-17 axis, and the gut microbiome in NAFLD. Specifically, they have demonstrated that IL-17 plays a critical role in progression of NAFLD to NASH in two mouse models and provide the first evidence regarding a microbe-driven IL-17 production in exacerbation of hepatocellular damage in NAFLD. Further studies are required to uncover the mechanisms by which IL-17 signaling induces hepatocyte injury and inflammation, the origin of the IL-17-producing cells, and the critical cell types expressing IL-17RA. One of the important aspects to study is regulation of IL-17 production by leptin, and the combined effect of these cytokines on NASH progression. Since both IL-17 and leptin are the few cytokines known to directly activate hepatic stellate cells/myofibroblasts,[24, 25] they might in fact synergistically facilitate development of hepatic fibrosis. Furthermore, one must establish the factors and possible feedback mechanism that regulate the microbiota-IL-17 interaction. Interestingly, recent studies have suggested that leptin regulates homeostasis of intestinal microflora. Finally, the role of IL-17 must be investigated in patients with NASH. If IL-17 mediates NASH in patients with the metabolic syndrome, it would open a new approach to therapy. Since many novel inhibitors of IL-17 have been developed and are successfully used to treat psoriasis, similar approaches could be beneficial as therapeutics for patients with NASH.
Tatiana Kisseleva, M.D., Ph.D.
Department of Surgery
UCSD, San Diego, CA