EDITORIAL Does Interleukin-17 Play the Villain in Nonalcoholic Steatohepatitis? See Article on page XXX.

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nterleukin (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.1 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.2 More recently, IL-17 has been implicated in liver, lung, and skin fibrosis, and in tumorigenesis.3 Mainly produced by CD41 Th17 cells,3-5 IL-17 mediates its biological function by way of signaling through a complex of IL-17RA and IL-17RC receptors.3 IL-17RA is ubiquitously expressed, but is rapidly and highly induced in hematopoietic cells6 and fibroblasts.7 IL-17 stimulates Kupffer cells/macrophages to express inflammatory cytokines IL-6, IL-1b, and tumor necrosis factor alpha (TNF-a) and profibrogenic transforming growth factor beta1 (TGF-b1) to directly induce activation of myofibroblasts. Further, deletion of IL-17RA in mice protects from liver fibrosis induced by cholestatic or toxic liver injury.8 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.9 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 Abbreviations: HFD, high-fat diet; HFHCD, high-fat high-carbohydrate diet; IL, interleukin; LPS, lipopolysaccharide; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; ROS, reactive oxygen species; SFB, segmented filamentous bacteria. Address reprint requests to: Tatiana Kisseleva, M.D., Ph.D., Department of Surgery, UCSD, 9500 Gilman Drive, CA 92093. E-mail: [email protected] C 2013 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26955 Potential conflict of interest: Nothing to report.

fibrosis, cirrhosis, and hepatocellular cancer.10 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.11 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.15 Harley at al.9 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.16 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.17 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,20 characterized over three decades ago, uniquely attach to the apical epithelium of small intestine.21 Mono-colonization of mice with SFB leads to immunological changes in mice, particularly within the small intestine.22 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-22.23 Consistently, Harley at al.9 1

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KISSELEVA

HEPATOLOGY, Month 2013

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.9 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-17producing cells, and the critical cell types expressing IL-17RA. One of the important aspects to study is regulation of IL-17 production by leptin,24 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.26 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

References 1. Iwakura Y, Ishigame H, Saijo S, Nakae S. Functional specialization of interleukin-17 family members. Immunity 2011;34:149-162. 2. Miossec P, Kolls JK. Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov 2012;11:763-776. 3. Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity 2004;21:467-476. 4. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-171 T helper cells. Cell 2006; 126:1121-1133.

5. Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 2008;28:29-39. 6. Yao Z, Fanslow WC, Seldin MF, Rousseau AM, Painter SL, Comeau MR, et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 1995;3:811-821. 7. Andoh A, Fujino S, Bamba S, Araki Y, Okuno T, Bamba T, et al. IL17 selectively down-regulates TNF-alpha-induced RANTES gene expression in human colonic subepithelial myofibroblasts. J Immunol 2002;169:1683-1687. 8. Meng F, Wang K, Aoyama T, Grivennikov SI, Paik Y, Scholten D, et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 2012;143:765-776 e761-763. 9. Harley IT, Stankiewicz TE, Giles DA, Softic S, Flick LM, Cappelletti M, et al. IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice. HEPATOLOGY 2013; doi: 10.1002/hep.26746. 10. Friedman SL. Liver fibrosis in 2012: convergent pathways that cause hepatic fibrosis in NASH. Nat Rev Gastroenterol Hepatol 2013;10:7172. 11. Das UN. Obesity: genes, brain, gut, and environment. Nutrition 2010; 26:459-473. 12. Zuniga EI, McGavern DB, Pruneda-Paz JL, Teng C, Oldstone MB. Bone marrow plasmacytoid dendritic cells can differentiate into myeloid dendritic cells upon virus infection. Nat Immunol 2004;5:12271234. 13. Ahmed M, Gaffen SL. IL-17 inhibits adipogenesis in part via C/EBPalpha, PPARgamma and Kruppel-like factors. Cytokine 2013;61:898905. 14. Ahmed M, Gaffen SL. IL-17 in obesity and adipogenesis. Cytokine Growth Factor Rev 2010;21:449-453. 15. Fabbrini E, Cella M, McCartney SA, Fuchs A, Abumrad NA, Pietka TA, et al. Association between specific adipose tissue CD41 T-cell populations and insulin resistance in obese individuals. Gastroenterology 2013;145:366-374 e361-363. 16. Duan J, Chung H, Troy E, Kasper DL. Microbial colonization drives expansion of IL-1 receptor 1-expressing and IL-17-producing gamma/ delta T cells. Cell Host Microbe 2010;7:140-150. 17. Krznaric Z, Vranesic Bender D, Kunovic A, Kekez D, Stimac D. Gut microbiota and obesity. Dig Dis 2012;30:196-200. 18. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature 2006;444:1022-1023. 19. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006;444:1027-1031. 20. Snel J, Heinen PP, Blok HJ, Carman RJ, Duncan AJ, Allen PC, et al. Comparison of 16S rRNA sequences of segmented filamentous bacteria isolated from mice, rats, and chickens and proposal of "Candidatus Arthromitus." Int J Syst Bacteriol 1995;45:780-782. 21. Reading NC, Kasper DL. The starting lineup: key microbial players in intestinal immunity and homeostasis. Front Microbiol 2011;2:148. 22. Umesaki Y, Okada Y, Matsumoto S, Imaoka A, Setoyama H. Segmented filamentous bacteria are indigenous intestinal bacteria that activate intraepithelial lymphocytes and induce MHC class II molecules and fucosyl asialo GM1 glycolipids on the small intestinal epithelial cells in the ex-germ-free mouse. Microbiol Immunol 1995;39:555-562. 23. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009;139:485-498. 24. Yu Y, Liu Y, Shi FD, Zou H, Matarese G, La Cava A. Cutting edge: leptininduced RORgammat expression in CD41 T cells promotes Th17 responses in systemic lupus erythematosus. J Immunol 2013;190:3054-3058. 25. Wang H, Lafdil F, Kong X, Gao B. Signal transducer and activator of transcription 3 in liver diseases: a novel therapeutic target. Int J Biol Sci 2011;7:536-550. 26. Clevers HC, Bevins CL. Paneth cells: maestros of the small intestinal crypts. Annu Rev Physiol 2013;75:289-311.

Does interleukin-17 play the villain in nonalcoholic steatohepatitis?

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