THE INFLUENCE OF THE IMMUNE RESPONSE ON LIVER FIBROSIS PROGRESSION IN CHRONIC LIVER DISEASES – A REVIEW ARTICLE
Keywords:
chronic hepatits C, non-alcoholic steatohepatitis, inflamation
Abstract
Chronic Liver Disease (CLD) is presented by continuous inflammation, destruction and regeneration of hepatocytes lasting more than six months. The progression leads to fibrosis, liver cirrhosis and, in the most severe cases, hepatocellular carcinoma (HCC).
The role of the immune system in CLD was recognized several decades ago, but not all the immune mechanisms of liver damage, which could be significant as potential therapeutic options, have been elucidated to date. Cytokines of the interleukin (IL)-23/IL-17 axis have been described as the key cytokines involved in the immunopathogenesis of CLD. Numerous studies have described the influence of the IL-23/IL-17 axis on the development of liver fibrosis with heterogeneous results. These results mainly described the pathophysiology, but also and potential immunotherapeutic options. The most contradictory results published in current studies concern chronic hepatitis C (HHC) and nonalcoholic steatohepatitis (NASH).
It is still unclear whether there are variations in local and systemic proinflammatory cytokine concentrations in HHC which can potentially guide immunotherapeutic strategies in these patients. On the other hand, in NASH inflammation is one of the key drivers of disease progression and development of fibrosis. The regulation of inflammation is controversial, depending on several intrahepatic and extrahepatic factors, and so far the mechanisms of immunopathogenesis have not been clearly revealed even in this chronic liver disease.
Further research is needed to clearly suggest whether some of the immunohepatotoxicity significant mechanisms in chronic liver diseases could be a potential prognostic and immunotherapeutic factor.
Key words: chronic hepatits C, non-alcoholic steatohepatitis, inflamation
References
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2. Poynard T, Mathurin P, Lai CL, Guyader D, Poupon R, Tainturier MH, Myers RP, Muntenau M, Ratziu V, Manns M, Vogel A, Capron F, Chedid A, Bedossa P. PANFIBROSIS Group. A comparison of fibrosis progression in chronic liver diseases. J Hepatol. 2003 Mar;38(3):257-65.
3. Bataller R, North KE, Brenner DA. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology. 2003 Mar;37(3):493-503.
4. Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017 Jul;14(7):397-411.
5. Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, Weissenborn K, Wong P. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014 Aug;60(2):715-35.
6. Buob S, Johnston AN, Webster CR. Portal hypertension: pathophysiology, diagnosis, and treatment. J Vet Intern Med. 2011 Mar-Apr;25(2):169-86. doi: 10.1111/j.1939-1676.2011.00691.x. PMID: 21382073.
7. Cheemerla, S.; Balakrishnan, M. Global Epidemiology of Chronic Liver Disease. Clin. Liver Dis. 2021, 17, 365–370.
8. Moon, A.M.; Singal, A.G.; Tapper, E.B. Contemporary Epidemiology of Chronic Liver Disease and Cirrhosis. Clin. Gastroenterol. Hepatol. 2020, 18, 2650–2666.
9. CDC National Vital Statistics Reports. July 2021. Available online: https://www.cdc.gov/nchs/nvss/leading-causes-of-death. htm (accessed on 26 July 2021).
10. Eslam, M.; Sanyal, A.J.; George, J.; International Consensus Panel. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology 2020, 158, 1999–2014.e1.
11. Dixon, J.B.; Bhathal, P.S.; O’Brien, P.E. Nonalcoholic fatty liver disease: Predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 2001, 121, 91–100.
12. Younossi, Z.M.; Golabi, P.; Paik, J.M.; Henry, A.; Van Dongen, C.; Henry, L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): A systematic review. Hepatology 2023, 77, 1335–1347.
13. Rinella, M.E.; Neuschwander-Tetri, B.A.; Siddiqui, M.S.; Abdelmalek, M.F.; Caldwell, S.; Barb, D.; Kleiner, D.E.; Loomba, R. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 2023, 77, 1797–1835.
14. Kountouras, J.; Kazakos, E.; Kyrailidi, F.; Polyzos, S.A.; Zavos, C.; Arapoglou, S.; Boziki, M.; Mouratidou, M.C.; TzitiridouChatzopoulou, M.; Chatzopoulos, D.; et al. Innate immunity and nonalcoholic fatty liver disease. Ann. Gastroenterol. 2023, 36, 244–256.
15. Yuan, L.; Hanlon, C.L.; Terrault, N.; Alqahtani, S.; Tamim, H.; Lai, M.; Saberi, B. Portrait of Regional Trends in Liver Transplantation for Nonalcoholic Steatohepatitis in the United States. Am. J. Gastroenterol. 2022, 117, 433–444.
16. Sebastiani, G.; Gkouvatsos, K.; Pantopoulos, K. Chronic hepatitis C and liver fibrosis. World J. Gastroenterol. 2014, 20, 11033–11053.
17. Sherlock, S. The immunology of liver disease. Am. J. Med. 1970, 49, 693–706.
18. Peters, M.; Vierling, J.; Gershwin, E.M.; Milich, D.; Chisari, F.V.; Hoofnagle, J.H.M.D. Immunology and the liver. Hepatology 1991, 13, 977–994.
19. Meng, P.; Zhao, S.; Niu, X.; Fu, N.; Su, S.; Wang, R.; Zhang, Y.; Qiao, L.; Nan, Y. Involvement of the Interleukin-23/Interleukin-17 Axis in Chronic Hepatitis C Virus Infection and Its Treatment Responses. Int. J. Mol. Sci. 2016, 17, 1070, Erratum in Int. J. Mol. Sci. 2016, 17, 1070.
20. Li, H.; Tsokos, G.C. IL-23/IL-17 Axis in Inflammatory Rheumatic Diseases. Clin. Rev. Allergy Immunol. 2021, 60, 31–45.
21. Cătană, C.S.; Berindan Neagoe, I.; Cozma, V.; Magda¸s, C.; Tăbăran, F.; Dumitra¸scu, D.L. Contribution of the IL-17/IL-23 axis to the pathogenesis of inflammatory bowel disease. World J. Gastroenterol. 2015, 21, 5823–5830.
22. Menter, A.; Krueger, G.G.; Paek, S.Y.; Kivelevitch, D.; Adamopoulos, I.E.; Langley, R.G. Interleukin-17 and Interleukin-23: A Narrative Review of Mechanisms of Action in Psoriasis and Associated Comorbidities. Dermatol. Ther. 2021, 11, 385–400.
23. Bankir, M.; Acik, D.Y. IL-17 and IL-23 levels in patients with early-stage chronic lymphocytic leukemia. North. Clin. Istanb. 2020, 8, 24–30.
24. Kolls, J.K.; Lindén, A. Interleukin-17 family members and inflammation. Immunity 2004, 21, 467–476.
25. Iwakura, Y.; Ishigame, H. The IL-23/IL-17 axis in inflammation. J. Clin. Investig. 2006, 116, 1218–1222.
26. Heredia, J.E.; Sorenson, C.; Flanagan, S.; Nunez, V.; Jones, C.; Martzall, A.; Leong, L.; Martinez, A.P.; Scherl, A.; Brightbill, H.D.; et al. IL-23 signaling is not an important driver of liver inflammation and fibrosis in murine non-alcoholic steatohepatitis models. PLoS ONE 2022, 17, e0274582.
27. Yan, S.; Wang, L.; Liu, N.; Wang, Y.; Chu, Y. Critical role of interleukin-17/interleukin-17 receptor axis in mediating Con A-induced hepatitis. Immunol. Cell Biol. 2012, 90, 421–428.
28. He, Y.; Hwang, S.; Ahmed, Y.A.; Feng, D.; Li, N.; Ribeiro, M.; Lafdil, F.; Kisseleva, T.; Szabo, G.; Gao, B. Immunopathobiology and therapeutic targets related to cytokines in liver diseases. Cell Mol. Immunol. 2021, 18, 18–37.
29. Krassenburg, L.A.P.; Maan, R.; Ramji, A.; Manns, M.P.; Cornberg, M.; Wedemeyer, H.; de Knegt, R.J.; Hansen, B.E.; Janssen, H.L.A.; de Man, R.A.; et al. Clinical outcomes following DAA therapy in patients with HCV-related cirrhosis depend on disease severity. J. Hepatol. 2021, 74, 1053–1063.
30. Lee, U.E.; Friedman, S.L. Mechanisms of hepatic fibrogenesis. Best Pract. Res. Clin. Gastroenterol. 2011, 25, 195–206.
31. Bălănescu, P.; Lădaru, A.; Voiosu, T.; Nicolau, A.; Ene, M.; Bălănescu, E. Th17 and IL-17 immunity in chronic hepatitis C infection. Rom. J. Intern. Med. 2012, 50, 13–18.
32. Rios, D.A.; Casciato, P.C.; Caldirola, M.S.; Gaillard, M.I.; Giadans, C.; Ameigeiras, B.; De Matteo, E.N.; Preciado, M.V.; Valva, P. Chronic Hepatitis C Pathogenesis: Immune Response in the Liver Microenvironment and Peripheral Compartment. Front. Cell. Infect. Microbiol. 2021, 11, 712105.
33. Falleti, E.; Fabris, C.; Toniutto, P.; Fontanini, E.; Cussigh, A.; Bitetto, D.; Fumolo, E.; Fornasiere, E.; Bragagnini, W.; Pinato, D.J.; et al. Interleukin-6 polymorphisms and gender: Relationship with the occurrence of hepatocellular carcinoma in patients with end-stage liver disease. Oncology 2009, 77, 304–313.
34. Paquissi, F.C. Immunity and Fibrogenesis: The Role of Th17/IL-17 Axis in HBV and HCV-induced Chronic Hepatitis and Progression to Cirrhosis. Front. Immunol. 2017, 8, 1195.
35. de Souza-Cruz, S.; Victória, M.B.; Tarragô, A.M.; da Costa, A.G.; Pimentel, J.P.; Pires, E.F.; Araújo, L.d.P.; Coelho-dos-Reis, J.G.; Gomes, M.d.S.; Amaral, L.R.; et al. Liver and blood cytokine microenvironment in HCV patients is associated to liver fibrosis score: A proinflammatory cytokine ensemble orchestrated by TNF and tuned by IL-10. BMC Microbiol. 2016, 16, 3.
36. El-Emshaty, H.M.; Nasif, W.A.; Mohamed, I.E. Serum Cytokine of IL-10 and IL-12 in Chronic Liver Disease: The Immune and Inflammatory Response. Dis. Markers 2015, 2015, 707254.
37. Owusu, D.O.; Phillips, R.; Owusu, M.; Sarfo, F.S.; Frempong, M. Increased levels of circulating IL-10 in persons recovered from hepatitis C virus (HCV) infection compared with persons with active HCV infection. BMC Res. Notes 2020, 13, 472.
38. Aboushousha, T.; Emad, M.; Rizk, G.; Ragab, K.; Hammam, O.; Fouad, R.; Helal, N.S. IL-4, IL-17 and CD163 Immunoexpression and IL-6 Gene Polymorphism in Chronic Hepatitis C Patients and Associated Hepatocellular Carcinoma. Asian Pac. J. Cancer Prev. 2021, 22, 1105–1113.
39. 53. Tan, Z.; Qian, X.; Jiang, R.; Liu, Q.; Wang, Y.; Chen, C.; Wang, X.; Ryffel, B.; Sun, B. IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation. J. Immunol. 2013, 191, 1835–1844.
40. Gomes, A.L.; Teijeiro, A.; Burén, S.; Tummala, K.S.; Yilmaz, M.; Waisman, A.; Theurillat, J.P.; Perna, C.; Djouder, N. Metabolic Inflammation-Associated IL-17A Causes Non-alcoholic Steatohepatitis and Hepatocellular Carcinoma. Cancer Cell 2016, 30, 161–175.
41. Chang, Q.; Wang, Y.K.; Zhao, Q.; Wang, C.Z.; Hu, Y.Z.; Wu, B.Y. Th17 cells are increased with severity of liver inflammation in patients with chronic hepatitis C. J. Gastroenterol. Hepatol. 2012, 27, 273–278.
42. Macek Jilkova, Z.; Afzal, S.; Marche, H.; Decaens, T.; Sturm, N.; Jouvin-Marche, E.; Huard, B.; Marche, P.N. Progression of fibrosis in patients with chronic viral hepatitis is associated with IL-17(+) neutrophils. Liver Int. 2016, 36, 1116–1124.
43. Santiago, A.M.; da Silva Graça Amoras, E.; Queiroz, M.A.F.; da Silva Conde, S.R.S.; Cayres-Vallinoto, I.M.V.; Ishak, R.; Vallinoto, A.C.R. TNFA -308G>A and IL10 -1082A>G polymorphisms seem to be predictive biomarkers of chronic HCV infection. BMC Infect. Dis. 2021, 21, 1133.
44. Tang, Y.; Bian, Z.; Zhao, L.; Liu, Y.; Liang, S.; Wang, Q.; Han, X.; Peng, Y.; Chen, X.; Shen, L.; et al. Interleukin-17 exacerbates hepatic steatosis and inflammation in non-alcoholic fatty liver disease. Clin. Exp. Immunol. 2011, 166, 281–290.
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2025/07/18
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