Cellular & Molecular Immunology (2017) 14, 143–145 & 2017 CSI and USTC All rights reserved 2042-0226/17 $32.00 www.nature.com/cmi

RESEARCH HIGHLIGHT

Interleukin-33 in the pathogenesis of liver fibrosis: alarming ILC2 and hepatic stellate cells

Ralf Weiskirchen1 and Frank Tacke2

Cellular & Molecular Immunology (2017) 14, 143–145; doi:10.1038/cmi.2016.62; published online 26 December 2016

nterleukin-33 (IL-33), a of employed a model of cholestatic fibrosis increase the production of inflammatory Ithe IL-1 family, has been implicated in and demonstrated a direct role for IL-33 only in injured livers.5 In the pathogenesis of liver fibrosis for quite in the profibrogenic activation of hepatic accordance with this role, recombinant some time. Indeed, IL-33 expression is stellate cells (Figure 1).5 First, the authors IL-33 aggravated hepatic fibrosis in upregulated in both human and murine confirmed that IL-33 is increased in bile experimental steatohepatitis, but had hepatic fibrosis.1,2 To date, it is believed duct ligation (BDL)-induced fibrosis in beneficial effects on hepatic steatosis.7 that IL-33 serves as an ‘alarmin’ released mice and in human cirrhotic liver tissue, In addition, Tan et al. provide experi- by stressed hepatocytes. IL-33 then which is in line with the current body of mental evidence that IL-33/ST2 signaling attracts type 2 innate lymphoid cells literature.1,2,6 Parenchymal cells (that is, is critical in activated hepatic stellate (ILC), which trigger the profibrogenic hepatocytes) were the primary cellular cells, the primary matrix-producing cells activation of hepatic stellate cells via source of IL-33. Second, they subjected in the liver. The stimulation of culture- mediators such as IL-13.1,3 IL-33 signals ST2-deficient mice to surgical BDL and activated hepatic stellate cells with through a unique IL-1 -related observed reduced hepatic injury, inflam- recombinant IL-33 increased the MAPK that is termed suppressor of mation, and fibrosis. This finding is pathways mediated by ERK, JNK and tumorigenicity 2 (ST2), also called similar to findings from toxic and dietary p38 protein kinases. This resulted in the IL-33R. The binding of IL-33 to ST2 fibrosis models that have been studied stimulation of α-smooth muscle actin activates nuclear factor-κB and mitogen- previously with ST2-deficient mice.1,7 and collagen expression.5 These data activated protein kinases (MAPKs) and Flow cytometry analysis further revealed suggest a direct profibrogenic role of drives the production of pro-infla- that, in the absence of ST2, BDL livers IL-33 in hepatic stellate cells, which is mmatory and T helper type 2 (Th2)- had a lower content of Th1 and Th2 cell potentially synergistic with its effects on associated cytokines.4 infiltrates and reduced neutrophil and innate lymphoid cells type 2 (ILC2).1 In the current issue of Cellular & numbers. In addition, the Although the current study and com- Molecular Immunology,Tanet al. upregulation of IL-33 during BDL was plementary fibrosis studies demonstrate positively correlated with an increase of overall profibrogenic effects in chronic type 2 ILCs. These data provide further injury models, studies in acute injury 1Institute of Molecular Pathobiochemistry, Experi- mental Therapy and Clinical Chemistry evidence for a link between IL-33 release settings sharply contradict this notion. (IFMPEGKC), University Hospital RWTH Aachen, and the secretion of type 2 inflamma- The application of concanavalin A Aachen D-52074, Germany. and 2Department of tory cytokines, such as IL-4, IL-5, IL-9 (Con A) induced more hepatic injury in Medicine III, University Hospital RWTH Aachen, and IL-13.8 IL-33-deficient mice compared to wild- Aachen D-52074, Germany. fl fi Correspondence: Professor R Weiskirchen, Insti- The relationship between in amma- type controls. Additionally, IL-33-de cient tute of Molecular Pathobiochemistry, Experimen- tion and IL-33 was further underpinned mice given Con A had significantly higher tal Gene Therapy and Clinical Chemistry by the finding that intraperitoneal injec- levels of -α and IL-1β (IFMPEGKC), University Hospital RWTH Aachen, Aachen D-52074, Germany. tions of recombinant IL-33 increased and a larger number of natural killer cells 9 E-mail: [email protected] hepatic inflammation in both naive and infiltrating the liver. Moreover, the injec- or Professor F Tacke, Department of Medicine III, BDL-injured livers when given 3 days tion of recombinant IL-33 had a protective University Hospital RWTH Aachen, Aachen prior to the BDL surgery. However, effect on hepatocytes by simultaneously D-52074, Germany. fl E-mail: [email protected] IL-33 alone failed to enhance the in am- repressing the expression of proapoptotic Received: 23 October 2016; Accepted: 23 matory response in sham-operated mice, and activating antiapoptotic genes. October 2016 suggesting that IL-33 has the capacity to IL-33 similarly protected hepatocytes in Research Highlight

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Figure 1 IL-33 in the pathogenesis of liver fibrosis. Crystal structure analysis has shown that the amino acids 112-270 of (IL)- 33 fold as a typical 12-stranded β-trefoil fold forming a β-barrel.19 In this issue of Cellular & Molecular Immunology,Tanet al. show that IL-33 expression is upregulated in the livers of mice subjected to bile duct ligation (BDL) and in patients suffering from cirrhosis. IL-33 is released by stressed hepatocytes as an alarmin and attracts innate lymphoid cells type 2 (ILC2) to the liver. Stimulation of cultured hepatic stellate cells (HSC) with IL-33 induces the expression of fibrogenic cytokines (that is, IL-6 and transforming (TGF)-β) and markers of hepatic fibrogenesis (that is, α-smooth muscle actin (α-SMA), collagen) in activated and transdifferentiated HSC (referred to as myofibroblasts (MFB)).5

mice that were subjected to 90 min of the pathogenesis of various liver diseases. the development of new therapeutics for partial hepatic ischemia followed by up to Moreover, sST2 could potentially serve as a patients with liver diseases. 8 h of reperfusion.10 These data suggest circulating biomarker to reflect IL-33 acti- that the release of IL-33 by injured hepa- vation and fibrosis in patients with liver CONFLICT OF INTEREST fl tocytes is a protective mechanism in acute diseases. In fact, sST2 serum levels differ The authors declare no con ict of interest. (and massive) liver damage, but that it between hepatitis B virus (HBV) infected ACKNOWLEDGEMENTS aggravates tissue fibrosis in chronic injury. patients with mild and severe fibrosis.16 Both authors are supported by the German These opposing functions need to be Similarly, the plasma levels of sST2 were Research Foundation (SFB/TRR 57) and the considered when developing new thera- found to be associated with disease severity Interdisciplinary Centre for Clinical Research 11 peutics intended to target this pathway. and mortality in patients with HBV-related (IZKF) within the Faculty of Medicine at the ST2, the IL-33 receptor, is highly con- acute-on-chronic liver failure. Elevated RWTH Aachen University. The authors thank served across species and is produced in concentrations of this decoy receptor Sabine Weiskirchen for preparing the figure. two isoforms from alternative 3' processing might indicate adverse prognosis in hepa- of mRNAs.12,13 The membrane-bound tocellular carcinoma.17,18 isoform (ST2L or IL1RL1-b) induces Since its discovery in 2005,4 it has 1 McHedlidze T, Waldner M, Zopf S, Walker J, immune responses after binding to IL-33, become evident that IL-33 is a versatile Rankin AL, Schuchmann M et al. Inter- while the soluble isoforms (soluble ST2 cytokine that influences the formation leukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity 2013; (sST2) or IL1RL1-a) act as a decoy recep- and severity of liver disease. The study by – 14 39:357 371. tor for IL-33. Tan et al. used a knockout Tan et al. emphasizes the crucial role of 2 Marvie P, Lisbonne M, L'helgoualc'h A, mouseinwhichthetargetingvector IL-33 in the formation of liver fibrosis. Rauch M, Turlin B, Preisser L et al. Inter- deleted the majority of exons 4 and 5 of This cytokine ‘alarms’ not only ILC2 but leukin-33 overexpression is associated with liver fibrosis in mice and humans. JCellMol the ST2 gene. These exons are common to also the collagen-producing hepatic stel- Med 2010; 14:1726–1739. both the membrane-bound and soluble late cells during chronic injury. These 3 Heymann F, Tacke F. Immunology in the – 15 liver from homeostasis to disease. Nat forms of the protein. It is speculated that data strongly support ongoing efforts to Rev Gastroenterol Hepatol 2016; 13: each receptor variant has a different role in target the IL-33/ST2 signaling pathway in 88–110.

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4 Schmitz J, Owyang A, Oldham E, Song Y, 9 Noel G, Arshad MI, Filliol A, Genet V, 15 Townsend MJ, Fallon PG, Matthews DJ, Jolin Murphy E, McClanahan TK et al. IL-33, an Rauch M, Lucas-Clerc C et al. Ablation of HE, McKenzie AN. T1/ST2-deficient mice interleukin-1-like cytokine that signals via interaction between IL-33 and ST2+ regulatory demonstrate the importance of T1/ST2 in the IL-1 receptor-related protein ST2 and T cells increases immune cell-mediated hepa- developing primary type 2 induces T helper type 2-associated cyto- titis and activated NK cell liver infiltration. Am responses. J Exp Med 2000; 191: kines. Immunity 2005; 23:479–490. J Physiol Gastrointest Liver Physiol 2016; 311: 1069–1076. 5 Tan Z, Liu Q, Jiang R, Lv L, Shoto SS, G313–G323. 16 Oztas E, Kuzu UB, Zengin NI, Kalkan IH, Maillet I et al. Interleukin-33 drives hepatic 10 Sakai N, Van Sweringen HL, Quillin RC, Onder FO, Yildiz H et al. Can serum ST2 fibrosis through activation of hepatic Schuster R, Blanchard J, Burns JM et al. levels be used as a marker of fibrosis in stellate cells. Cell Mol Immunol 2016 Interleukin-33 is hepatoprotective during chronic hepatitis B infection? Medicine (Bal- (this issue). liver ischemia/reperfusion in mice. Hepatol- timore) 2015; 94:e1889. 6 Ming D, Yu X, Guo R, Deng Y, Li J, Lin C ogy 2012; 56:1468–1478. 17 Lei Z, Mo Z, Zhu J, Pang X, Zheng X, Wu Z et al. Elevated TGF-β1/IL-31 pathway is 11 Weiskirchen R, Tacke F. Liver fibrosis: from et al. Soluble ST2 plasma concentrations associated with the disease severity of Hepa- pathogenesis to novel therapies. Dig Dis predict mortality in HBV-related acute-on- titis B virus-related liver cirrhosis. Viral 2016; 34:410–422. chronic liver failure. Mediators Inflamm Immunol 2015; 28:209–216. 12 Gächter T, Werenskiold AK, Klemenz R. 2015; 2015: 535938. 7 Gao Y, Liu Y, Yang M, Guo X, Zhang M, Li H Transcription of the interleukin-1 receptor- 18 Bergis D, Kassis V, Ranglack A, Koeberle V, et al. IL-33 treatment attenuated diet- related T1 gene is initiated at different Piiper A, Kronenberger B et al. High serum induced hepatic steatosis but aggravated promoters in mast cells and fibroblasts. levels of the Interleukin-33 receptor soluble hepatic fibrosis. Oncotarget 2016; 7: JBiolChem1996; 271:124–129. ST2 as a negative prognostic factor in 33649–33661. 13 Kakkar R, Lee RT. The IL-33/ST2 pathway: hepatocellular carcinoma. Transl Oncol 8 Vannella KM, Ramalingam TR, Borthwick therapeutic target and novel biomarker. Nat 2013; 6:311–318. LA, Barron L, Hart KM, Thompson RW et Rev Drug Discov 2008; 7:827–840. 19 Liu X, Hammel M, He Y, Tainer JA, Jeng US, al. Combinatorial targeting of TSLP, IL-25, 14 Hammerich L, Tacke F. in Zhang L et al. Structural insights into the and IL-33 in type 2 cytokine-driven inflam- chronic liver disease: lessons learned from interaction of IL-33 with its receptors. mation and fibrosis. Sci Transl Med 2016; experimental mouse models. Clin Exp Gas- Proc Natl Acad Sci USA 2013; 110: 8:337ra65. troenterol 2014; 7:297–306. 14918–14923.

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