Abstract
Liver fibrosis and its end-stage consequence, cirrhosis, represent the final common pathway of virtually all chronic liver diseases. Research into hepatic stellate cell activation, imbalance of the extracellular matrix synthesis and degradation and the contribution of cytokines and chemokines has further elucidated the mechanisms underlying fibrosis. Furthermore, clarification of changes in host adaptive and innate immune systems has accelerated our understanding of the association between liver inflammation and fibrosis. Continued elucidation of the mechanisms of hepatic fibrosis has provided a comprehensive model of fibrosis progression and regression. This review summarizes the current concepts of improvements that have been made in the field of fibrosis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Buy this article
Purchase on Springer Link
Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Balabaud C, Bioulac-Sage P, Desmouliere A . The role of hepatic stellate cells in liver regeneration. J Hepatol 2004; 40: 1023–1026.
Hernandez-Gea V, Friedman SL . Pathogenesis of liver fibrosis. Annu Rev Pathol 2010; 6: 425–456.
Sangiovanni A, Prati GM, Fasani P . The natural history of compensated cirrhosis due to hepatitis C virus: a 17-year cohort study of 214 patients. Hepatology 2006; 43: 1303–1310.
Fattovich G, Giustina G, Degos F, Tremolada F, Diodati G, Almasio P et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up of 384 patients. Gastroenterology 1997; 112: 463–472.
Desmet VJ, Roskams T . Cirrhosis reversal: a duel between dogma and myth. J Hepatol 2004; 40: 860–867.
Iredale JP . Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 1998; 102: 538–549.
Fallowfield JA, Iredale JP . Targeted treatments for cirrhosis. Expert Opin Ther Targets 2004; 8: 423–435.
Blomhoff R, Berg T . Isolation and cultivation of rat liver stellate cells. Methods Enzymol 1990; 190: 58–71.
Friedman SL . Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem 2000; 275: 2247–2250.
Alison MR, Vig P, Russo F, Bigger BW, Amofah E, Themis M et al. Hepatic stem cells: from inside and outside the liver? Cell Prolif 2004; 37: 1–21.
Wake K . Three-dimensional structure of the sinusoidal wall in the liver: a Golgi study. Prog Clin Biol Res 1989; 295: 257–262.
Gressner AM, Weiskirchen R . Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med 2006; 10: 76–99.
Bataller R, Brenner DA . Liver fibrosis. J Clin Invest 2005; 115: 209–218.
Cassiman D, Libbrecht L, Desmet V, Denef C, Roskams T . Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers. J Hepatol 2002; 36: 200–209.
Gores GJ, Kaufmann SH . Is TRAIL hepatotoxic? Hepatology 2001; 34: 3–6.
Fischer R . Cariers A, Reinehr R, Häussinger D. Caspase 9-dependent killing of hepatic stellate cells by activated Kupffer cells. Gastroenterology 2002; 123: 845–861.
Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA . Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide (LPS) in human hepatic stellate cells. Hepatology 2003; 37: 1043–1055.
Elsharkawy AM, Oakley F, Mann DA . The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. Apoptosis 2005; 10: 927–939.
Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley S et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 1998; 102: 538–549.
Hernandez-Gea V, Friedman SL . Pathogenesis of liver fibrosis. Annu Rev Pathol 2011; 6: 425–456.
Higashiyama R, Moro T, Nakao S, Mikami K, Fukumitsu H, Ueda Y et al. Negligible contribution of bone marrow-derived cells to collagen production during hepatic fibrogenesis in mice. Gastroenterology 2009; 137: 1459–1466.
Kalluri R, Neilson EG . Epithelial–mesenchymal transition and its implications for fibrosis. J Clin Invest 2003; 112: 1776–1784.
Geerts A . History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis 2001; 21: 311–335.
Schuppan D, Ruehl M, Somasundaram R, Hahn EG . Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis 2011; 21: 351–372.2001;
Ohuchi E, Imai K, Fujii Y, Sato H, Seiki M, Okada Y . Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J Biol Chem 1997; 272: 2446–2451.
Aimes RT, Quigley JP . Matrix metalloproteinase-2 is an interstitial collagenase—inhibitor-free enzyme catalyzes the cleavage of collagen fibrils and soluble native type I collagen generating the specific 3/4- and 1/4-length fragments. J Biol Chem 1995; 270: 5872–5876.
Benyon RC, Iredale JP, Goddard S, Winwood PJ, Arthur MJ . Expression of tissue inhibitor of metalloproteinases-1 and -2 is increased in fibrotic human liver. Gastroenterology 1996; 110: 821–831.
Arthur MJ, Fibrosigenesis II . Metalloproteinases and their inhibitors in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 2000; 279: 4820–4828.
Maher JJ . Interactions between hepatic stellate cells and the immune system. Semi Liver Dis 2001; 21: 417–426.
McGaha TL, Bona CA . Role of profibrogenic cytokines secreted by T cells in fibrotic processes in scleroderma. Autoimmun Rev 2002; 1: 174–181.
Pinzani M, Vizzutti F . Fibrosis and cirrhosis reversibility: clinical features and implications. Clin Liver Dis 2008; 12: 901–913.
Mahmood S, Sho M, Yasuhara Y, Kawanaka M, Niiyama G, Togawa K et al. Clinical significance of intrahepatic interleukin-8 in chronic hepatitis C patients. Hepatol Res 2002; 24: 413–419.
Imamura M, Ogawa T, Sasaguri Y, Chayama K, Ueno H . Suppression of macrophage infiltration inhibits activation of hepatic stellate cells and liver fibrogenesis in rats. Gastroenterology 2005; 128: 138–146.
Schwabe RF, Bataller R, Brenner DA . Human hepatic stellate cells express CCR5 and RANTES to induce proliferation and migration. Am J Physiol Gastrointest Liver Physiol 2003; 285: G949–G958.
Zeremski M, Petrovic LM, Chiriboga L, Brown QB, Yee HT, Kinkhabwala M et al. Intrahepatic levels of CXCR3-associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C. Hepatology 2008; 48: 1440–1450.
Bonacchi A, Petrai I, Defranco RM, Lazzeri E, Annunziato F, Efsen E et al. The chemokine CCL21 modulates lymphocyte recruitment and fibrosis in chronic hepatitis C. Gastroenterology 2003; 125: 1060–1076.
Hong F, Tuyama A, Lee TF, Loke J, Agarwal R, Cheng X et al. Hepatic stellate cells express functional CXCR4: role in stromal cell-derived factor-1alpha-mediated stellate cell activation. Hepatology 2009; 49: 2055–2067.
Seki E, de Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 2007; 13: 1324–1332.
Huang H, Shiffman ML, Friedman S, Venkatesh R, Bzowej N, Abar OT et al. A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology 2007; 46: 297–306.
Guo J, Loke J, Zheng F, Hong F, Yea S, Fukata M et al. Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of Toll-like receptor 4 to hepatic stellate cell responses. Hepatology 2009; 49: 960–968.
Watanabe A, Hashmi A, Gomes DA, Town T, Badou A, Flavell RA et al. Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9. Hepatology 2007; 46: 1509–1518.
Gäbele E, Mühlbauer M, Dorn C, Weiss TS, Froh M, Schnabl B et al. Role of TLR9 in hepatic stellate cells and experimental liver fibrosis. Biochem Biophys Res Commun 2008; 376: 271–276.
Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S et al. Selective depletion of macrophages reveals distinct opposing roles during liver injury and repair. J Clin Invest 2005; 115: 56–65.
Rivera CA, Bradford BU, Hunt KJ, Adachi Y, Schrum LW, Koop DR et al. Attenuation of CCl4-induced hepatic fibrosis by GdCl3 treatment or dietary glycine. Am J Physiol Gastrointest Liver Physiol 2002; 281: G200–G207.
Ricardo SD, van Goor H, Eddy AA . Macrophage diversity in renal injury and repair. J Clin Invest 2008; 118: 3522–3530.
Taimr P, Higuchi H, Kocova E, Rippe RA, Friedman S, Gores GJ . Activated stellate cells express the TRAIL receptor-2/death receptor-5 and undergo TRAIL-mediated apoptosis. Hepatology 2003; 37: 87–95.
Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C et al. Senescence of activated stellate cells limits liver fibrosis. Cell 2008; 134: 657–667.
Radaeva S, Sun R, Jaruga B, Nguyen VT, Tian Z, Gao B . Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis inducing ligand-dependent manners. Gastroenterology 2006; 130: 435–452.
Dunn C, Brunetto M, Reynolds G, Christophides T, Kennedy PT, Lampertico P et al. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med 2007; 204: 667–680.
Morishima C, Paschal DM, Wang CC, Yoshihara CS, Wood BL, Yeo AE et al. Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing. Hepatology 2006; 43: 573–580.
Bonecchi R, Facchetti F, Dusi S, Luini W, Lissandrini D, Simmelink M et al. Induction of functional IL-8 receptors by IL-4 and IL-13 in human monocytes. J Immunol 2000; 164: 3862–3869.
Connolly MK, Bedrosian AS, Mallen-St Clair J, Mitchell AP, Ibrahim J, Stroud A et al. In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-α. J Clin Invest 2009; 119: 3213–3225.
de Lalla C, Galli G, Aldrighetti L, Romeo R, Mariani M, Monno A et al. Production of profibrotic cytokines by invariant NKT cells characterizes cirrhosis progression in chronic viral hepatitis. J Immunol 2004; 117: 3417–3425.
Connolly MK, Bedrosian AS, Mallen-St Clair J, Mitchell AP, Ibrahim J, Stroud A et al. In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-α. J Clin Invest 2009; 119: 3213–3225.
Hillebrandt S, Wasmuth HE, Weiskirchen R, Hellerbrand C, Keppeler H, Werth A et al. Complement factor 5 is a quantitative trait gene that modifies liver. Nat Genet 2005; 37: 835–843.
Schlaf G, Schmitz M, Heine I, Demberg T, Schieferdecker HL, Götze O . Upregulation of fibronectin but not of entactin, collagen IV and smooth muscle actin by anaphylatoxin C5a in rat hepatic stellate cells. Histol Histopathol 2004; 19: 1165–1174.
Mastellos D, Papadimitriou JC, Franchini S, Tsonis PA, Lambris JD . A novel role of complement: mice deficient in the fifth component of complement (C5) exhibit impaired liver regeneration. J Immunol 2001; 166: 2479–2486.
Bykov I, Junnikkala S, Pekna M, Lindros KO, Meri S . Complement C3 contributes to ethanol-induced liver steatosis in mice. Ann Med 2006; 38: 280–286.
Bugdaci MS, Alkim C, Karaca C, Kesici B, Bayraktar B, Sokmen M . Could complement C4 be an alternative to biopsy for chronic hepatitis b histopathologic findings? J Clin Gastroenterol 2011; 45: 449–455.
Cheever AW, Williams ME, Wynn TA, Finkelman FD, Seder RA, Cox TM et al. Anti-IL-4 treatment of Schistosoma mansoni-infected mice inhibits development of T cells and non-B, non-T cells expressing Th2 cytokines while decreasing egg-induced hepatic fibrosis. J Immunol 1994; 153: 753–759.
Chiaramonte MG, Donaldson DD, Cheever AW, Wynn TA . An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. J Clin Invest 1999; 104: 777–785.
Novobrantseva TI, Majeau GR, Amatucci A, Kogan S, Brenner I, Casola S et al. Attenuated liver fibrosis in the absence of B cells. J Clin Invest 2005; 115: 3072–3082.
Acknowledgements
This work was supported by a grant from the National Natural Science Foundation of China (No. 31170865).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no financial or commercial conflict of interest.
Rights and permissions
About this article
Cite this article
Xu, R., Zhang, Z. & Wang, FS. Liver fibrosis: mechanisms of immune-mediated liver injury. Cell Mol Immunol 9, 296–301 (2012). https://doi.org/10.1038/cmi.2011.53
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/cmi.2011.53
Keywords
This article is cited by
-
Regulatory T cells (Tregs) in liver fibrosis
Cell Death Discovery (2023)
-
Investigating the effects of chronic low-dose radiation exposure in the liver of a hypothermic zebrafish model
Scientific Reports (2023)
-
Mesenchymal stem cells-based therapy in liver diseases
Molecular Biomedicine (2022)
-
HOXB13 expression is correlated with hepatic inflammatory activity of patients with hepatic fibrosis
Journal of Molecular Histology (2020)
-
Diethylcarbamazine attenuates the expression of pro-fibrogenic markers and hepatic stellate cells activation in carbon tetrachloride-induced liver fibrosis
Inflammopharmacology (2018)