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Dywicki J, Buitrago-Molina LE, Noyan F, et al. The Detrimental Role of Regulatory T Cells in Nonalcoholic Steatohepatitis. Hepatol Commun. 2021;doi: 10.1002/hep4.1807.
Dywicki, J., Buitrago-Molina, L. E., Noyan, F., Davalos-Misslitz, A. C., Hupa-Breier, K. L., Lieber, M., Hapke, M., Schlue, J., Falk, C. S., Raha, S., Prinz, I., Koenecke, C., Manns, M. P., Wedemeyer, H., Hardtke-Wolenski, M., & Jaeckel, E. (2021). The Detrimental Role of Regulatory T Cells in Nonalcoholic Steatohepatitis. Hepatology communications, . https://doi.org/10.1002/hep4.1807
Dywicki, Janine, et al. "The Detrimental Role of Regulatory T Cells in Nonalcoholic Steatohepatitis." Hepatology communications vol. (2021). doi: https://doi.org/10.1002/hep4.1807
Dywicki J, Buitrago-Molina LE, Noyan F, Davalos-Misslitz AC, Hupa-Breier KL, Lieber M, Hapke M, Schlue J, Falk CS, Raha S, Prinz I, Koenecke C, Manns MP, Wedemeyer H, Hardtke-Wolenski M, Jaeckel E. The Detrimental Role of Regulatory T Cells in Nonalcoholic Steatohepatitis. Hepatol Commun. 2021 Aug 25; doi: 10.1002/hep4.1807. Epub 2021 Aug 25. PMID: 34532981.
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Hepatol Commun. 2021 Aug 25; doi: 10.1002/hep4.1807. Epub 2021 Aug 25.

The Detrimental Role of Regulatory T Cells in Nonalcoholic Steatohepatitis.

Hepatology communications

Janine Dywicki, Laura Elisa Buitrago-Molina, Fatih Noyan, Ana C Davalos-Misslitz, Katharina L Hupa-Breier, Maren Lieber, Martin Hapke, Jerome Schlue, Christine S Falk, Solaiman Raha, Immo Prinz, Christian Koenecke, Michael P Manns, Heiner Wedemeyer, Matthias Hardtke-Wolenski, Elmar Jaeckel

Affiliations

  1. Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.
  2. Department of Gastroenterology and Hepatology, Essen University Hospital, University Duisburg-Essen, Essen, Germany.
  3. Institute of Pathology, Hannover Medical School, Hannover, Germany.
  4. Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany.
  5. Institute of Immunology, Hannover Medical School, Hannover, Germany.
  6. Institute of Systems Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  7. Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

PMID: 34532981 DOI: 10.1002/hep4.1807

Abstract

Nonalcoholic steatohepatitis (NASH) is induced by steatosis and metabolic inflammation. While involvement of the innate immune response has been shown, the role of the adaptive immune response in NASH remains controversial. Likewise, the role of regulatory T cells (Treg) in NASH remains unclear although initial clinical trials aim to target these regulatory responses. High-fat high-carbohydrate (HF-HC) diet feeding of NASH-resistant BALB/c mice as well as the corresponding recombination activating 1 (Rag)-deficient strain was used to induce NASH and to study the role of the adaptive immune response. HF-HC diet feeding induced strong activation of intrahepatic T cells in BALB/c mice, suggesting an antigen-driven effect. In contrast, the effects of the absence of the adaptive immune response was notable. NASH in BALB/c Rag1

© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

References

  1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73-84. - PubMed
  2. Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018;15:11-20. - PubMed
  3. Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013;10:330-344. - PubMed
  4. Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015;148:547-555. - PubMed
  5. Golabi P, Bush H, Stepanova M, Locklear CT, Jacobson IM, Mishra A, et al. Liver transplantation (LT) for cryptogenic cirrhosis (CC) and nonalcoholic steatohepatitis (NASH) cirrhosis: data from the Scientific Registry of Transplant Recipients (SRTR): 1994 to 2016. Medicine (Baltimore) 2018;97:e11518. - PubMed
  6. Tosello-Trampont AC, Landes SG, Nguyen V, Novobrantseva TI, Hahn YS. Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-alpha production. J Biol Chem 2012;287:40161-40172. - PubMed
  7. Malehmir M, Pfister D, Gallage S, Szydlowska M, Inverso D, Kotsiliti E, et al. Platelet GPIbalpha is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat Med 2019;25:641-655. - PubMed
  8. Gadd VL, Skoien R, Powell EE, Fagan KJ, Winterford C, Horsfall L, et al. The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology 2014;59:1393-1405. - PubMed
  9. Sutti S, Albano E. Adaptive immunity: an emerging player in the progression of NAFLD. Nat Rev Gastroenterol Hepatol 2020;17:81-92. - PubMed
  10. Rau M, Schilling A-K, Meertens J, Hering I, Weiss J, Jurowich C, et al. Progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis is marked by a higher frequency of Th17 cells in the liver and an increased Th17/resting regulatory T cell ratio in peripheral blood and in the liver. J Immunol 2016;196:97-105. - PubMed
  11. Harley ITW, 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 2014;59:1830-1839. - PubMed
  12. Ma X, Hua J, Mohamood AR, Hamad AR, Ravi R, Li Z. A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury. Hepatology 2007;46:1519-1529. - PubMed
  13. Wolf M, Adili A, Piotrowitz K, Abdullah Z, Boege Y, Stemmer K, et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 2014;26:549-564. - PubMed
  14. Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature 2016;531:253-257. - PubMed
  15. Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 2009;15:921-929. - PubMed
  16. Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 2009;15:930-939. - PubMed
  17. Rinella ME, Elias MS, Smolak RR, Fu T, Borensztajn J, Green RM. Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet. J Lipid Res 2008;49:1068-1076. - PubMed
  18. Rinella ME, Green RM. The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance. J Hepatol 2004;40:47-51. - PubMed
  19. Hardtke-Wolenski M, Fischer K, Noyan F, Schlue J, Falk CS, Stahlhut M, et al. Genetic predisposition and environmental danger signals initiate chronic autoimmune hepatitis driven by CD4+ T cells. Hepatology 2013;58:718-728. - PubMed
  20. Römermann D, Ansari N, Schultz-Moreira AR, Michael A, Marhenke S, Hardtke-Wolenski M, et al. Absence of Atg7 in the liver disturbed hepatic regeneration after liver injury. Liver Int 2020;40:1225-1238. - PubMed
  21. Buitrago-Molina LE, Dywicki J, Noyan F, Trippler M, Pietrek J, Schlue J, et al. Splenectomy prior to experimental induction of autoimmune hepatitis promotes more severe hepatic inflammation, production of IL-17 and apoptosis. Biomedicines 2021;9:58. - PubMed
  22. Buitrago-Molina LE, Pietrek J, Noyan F, Schlue J, Manns MP, Wedemeyer H, et al. Treg-specific IL-2 therapy can reestablish intrahepatic immune regulation in autoimmune hepatitis. J Autoimmun 2021;117:102591. - PubMed
  23. Assarsson E, Lundberg M, Holmquist G, Björkesten J, Thorsen SB, Ekman D, et al. Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS One 2014;9:e95192. - PubMed
  24. Schultz Moreira AR, Rüschenbaum S, Schefczyk S, Hendgen-Cotta U, Rassaf T, Broering R, et al. 9-PAHSA prevents mitochondrial dysfunction and increases the viability of steatotic hepatocytes. Int J Mol Sci 2020;21:8279. - PubMed
  25. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al.; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313-1321. - PubMed
  26. Dywicki J, Buitrago-Molina LE, Pietrek J, Lieber M, Broering R, Khera T, et al. Autoimmune hepatitis induction can occur in the liver. Liver Int 2020;40:377-381. - PubMed
  27. Ju C, Tacke F. Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies. Cell Mol Immunol 2016;13:316-327. - PubMed
  28. Rahman K, Vengrenyuk Y, Ramsey SA, Vila NR, Girgis NM, Liu J, et al. Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression. J Clin Invest 2017;127:2904-2915. - PubMed
  29. Duvallet E, Semerano L, Assier E, Falgarone G, Boissier MC. Interleukin-23: a key cytokine in inflammatory diseases. Ann Med 2011;43:503-511. - PubMed
  30. Chatenoud L. Immune therapy for type 1 diabetes mellitus-what is unique about anti-CD3 antibodies? Nat Rev Endocrinol 2010;6:149-157. - PubMed
  31. Adams LA, Lindor KD. Nonalcoholic fatty liver disease. Ann Epidemiol 2007;17:863-869. - PubMed
  32. Peiseler M, Sebode M, Franke B, Wortmann F, Schwinge D, Quaas A, et al. FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency. J Hepatol 2012;57:125-132. - PubMed
  33. Taubert R, Hardtke-Wolenski M, Noyan F, Wilms A, Baumann AK, Schlue J, et al. Intrahepatic regulatory T cells in autoimmune hepatitis are associated with treatment response and depleted with current therapies. J Hepatol 2014;61:1106-1114. - PubMed
  34. Taubert R, Pischke S, Schlue J, Wedemeyer H, Noyan F, Heim A, et al. Enrichment of regulatory T cells in acutely rejected human liver allografts. Am J Transplant 2012;12:3425-3436. - PubMed
  35. Hardtke-Wolenski M, Taubert R, Noyan F, Sievers M, Dywicki J, Schlue J, et al. Autoimmune hepatitis in a murine autoimmune polyendocrine syndrome type 1 model is directed against multiple autoantigens. Hepatology 2015;61:1295-1305. - PubMed
  36. Zhou S-L, Zhou Z-J, Hu Z-Q, Huang X-W, Wang Z, Chen E-B, et al. Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology 2016;150:1646-1658.e17. - PubMed
  37. Farrell GC, Mridha AR, Yeh MM, Arsov T, Van Rooyen DM, Brooling J, et al. Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype. Liver Int 2014;34:1084-1093. - PubMed
  38. Chung KJ, Nati M, Chavakis T, Chatzigeorgiou A. Innate immune cells in the adipose tissue. Rev Endocr Metab Disord 2018;19:283-292. - PubMed
  39. Wei Y, Tian Q, Zhao X, Wang X. Serum transforming growth factor beta 3 predicts future development of nonalcoholic fatty liver disease. Int J Clin Exp Med 2015;8:4545-4550. - PubMed
  40. Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010;51:121-129. - PubMed
  41. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015;149:367-378.e5. - PubMed

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