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Z Gastroenterol 2023; 61(01): 76-82
DOI: 10.1055/a-1993-3519
Übersicht

Angeborene und erworbene Immunität im Kontext der nichtalkoholischen Fettlebererkrankung

Innate and adaptive immunity in the context of non-alcoholic fatty liver disease
Bernd Heinrich 
1   Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany (Ringgold ID: RIN9177)
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Zusammenfassung

Die nichtalkoholische Fettlebererkrankung (NAFLD) ist ein wachsendes Gesundheitsproblem. Das Verständnis der immunologischen Vorgänge in der Leber während der Ausbildung sowie Progression der Fettlebererkrankung hin zu einer Fettleberentzündung (NASH), Leberzirrhose oder hepatozellulärem Karzinom (HCC) kann dabei zum besseren Erkrankungsverständnis, Identifizierung von klinisch relevanten Subgruppen sowie therapeutischen Ansätzen genutzt werden. Die Interaktion zwischen angeborenem und erworbenem Immunsystem scheint dabei von großer Wichtigkeit zu sein. Dieser Übersichtsartikel beleuchtet die verschiedenen immunologischen Vorgänge in der NAFLD bis hin zur Progression zum HCC, geordnet nach den wesentlichen Zellgruppen des angeborenen und erworbenen Immunsystems.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a growing health problem. Understanding the immunological processes in the liver during the development and progression of fatty liver disease to fatty liver inflammation (NASH), liver cirrhosis or hepatocellular carcinoma (HCC) can be used to better understand the disease, identify clinically relevant subgroups and therapeutic approaches. The interaction between innate and acquired immune systems seems to be of great importance. This review article highlights the various immunological processes in NAFLD leading up to progression to HCC, organized according to the major cell groups of the innate and acquired immune systems.

Schlüsselwörter

NAFLD - NASH - HCC - Angeborenes Immunsystem - Erworbenes Immunsystem

Keywords

NAFLD - NASH - HCC - Immunsystem - Zytokine


Publication History

Received: 04 October 2022

Accepted after revision: 04 December 2022

Article published online:
09 January 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • Literatur

  • 1 Estes C, Anstee QM, Arias-Loste MT. et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. Journal of hepatology 2018; 69 (04) 896-904
    CrossrefPubMedSearch in Google Scholar
  • 2 Estes C, Razavi H, Loomba R. et al. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology (Baltimore, Md) 2018; 67 (01) 123-133
    CrossrefPubMedSearch in Google Scholar
  • 3 Yki-Järvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol 2014; 2 (11) 901-910
    CrossrefPubMedSearch in Google Scholar
  • 4 van Kleef LA, Sonneveld MJ, Kavousi M. et al. Fatty liver disease is not associated with increased mortality in the elderly: A prospective cohort study. Hepatology (Baltimore, Md) 2022;
    CrossrefPubMedSearch in Google Scholar
  • 5 Chalasani N, Younossi Z, Lavine JE. et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology (Baltimore, Md) 2018; 67 (01) 328-357
    CrossrefPubMedSearch in Google Scholar
  • 6 Roeb E, Canbay A, Bantel H. et al. Aktualisierte S2k-Leitlinie nicht-alkoholische Fettlebererkrankung der Deutschen Gesellschaft für Gastroenterologie, Verdauungs-und Stoffwechselkrankheiten (DGVS)–April 2022–AWMF-Registernummer: 021–025. Zeitschrift fur Gastroenterologie 2022; 60 (09) 1346-1421
    Thieme ConnectPubMedSearch in Google Scholar
  • 7 Huby T, Gautier EL. Immune cell-mediated features of non-alcoholic steatohepatitis. Nature reviews Immunology 2022; 22 (07) 429-443
    CrossrefPubMedSearch in Google Scholar
  • 8 Heinrich B, Brown ZJ, Diggs LP. et al. Steatohepatitis Impairs T-cell-Directed Immunotherapies Against Liver Tumors in Mice. Gastroenterology 2021; 160 (01) 331-345 e6
    CrossrefPubMedSearch in Google Scholar
  • 9 Dudek M, Pfister D, Donakonda S. et al. Auto-aggressive CXCR6(+) CD8 T cells cause liver immune pathology in NASH. Nature 2021; 592: 444-449
    CrossrefPubMedSearch in Google Scholar
  • 10 Ma C, Kesarwala AH, Eggert T. et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature 2016; 531: 253-257
    CrossrefPubMedSearch in Google Scholar
  • 11 Brown ZJ, Heinrich B, Greten TF. Mouse models of hepatocellular carcinoma: an overview and highlights for immunotherapy research. Nat Rev Gastroenterol Hepatol 2018; 15 (09) 536-554
    CrossrefPubMedSearch in Google Scholar
  • 12 Im YR, Hunter H, de Gracia Hahn D. et al. A Systematic Review of Animal Models of NAFLD Finds High-Fat, High-Fructose Diets Most Closely Resemble Human NAFLD. Hepatology (Baltimore, Md) 2021; 74 (04) 1884-1901
    CrossrefPubMedSearch in Google Scholar
  • 13 Machado MV, Michelotti GA, Xie G. et al. Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease. PloS one 2015; 10 (05) e0127991
    CrossrefPubMedSearch in Google Scholar
  • 14 Tsuchida T, Lee YA, Fujiwara N. et al. A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. Journal of hepatology 2018; 69 (02) 385-395
    CrossrefPubMedSearch in Google Scholar
  • 15 Alisi A, Carsetti R, Nobili V. Pathogen- or damage-associated molecular patterns during nonalcoholic fatty liver disease development. Hepatology (Baltimore, Md) 2011; 54 (05) 1500-1502
    CrossrefPubMedSearch in Google Scholar
  • 16 Arrese M, Cabrera D, Kalergis AM. et al. Innate Immunity and Inflammation in NAFLD/NASH. Digestive diseases and sciences 2016; 61 (05) 1294-1303
    CrossrefPubMedSearch in Google Scholar
  • 17 Dallio M, Sangineto M, Romeo M. et al. Immunity as Cornerstone of Non-Alcoholic Fatty Liver Disease: The Contribution of Oxidative Stress in the Disease Progression. International journal of molecular sciences 2021; 22 (01) 436
    CrossrefPubMedSearch in Google Scholar
  • 18 Shi FD, Ljunggren HG, La Cava A. et al. Organ-specific features of natural killer cells. Nature reviews Immunology 2011; 11 (10) 658-671
    CrossrefPubMedSearch in Google Scholar
  • 19 Chen Y, Tian Z. Roles of Hepatic Innate and Innate-Like Lymphocytes in Nonalcoholic Steatohepatitis. Front Immunol 2020; 11: 1500
    CrossrefPubMedSearch in Google Scholar
  • 20 Riggan L, Freud AG, O’Sullivan TE. True Detective: Unraveling Group 1 Innate Lymphocyte Heterogeneity. Trends in immunology 2019;
    CrossrefPubMedSearch in Google Scholar
  • 21 Vivier E, Artis D, Colonna M. et al. Innate Lymphoid Cells: 10 Years On. Cell 2018; 174 (05) 1054-1066
    CrossrefPubMedSearch in Google Scholar
  • 22 Zhang X, Shen J, Man K. et al. CXCL10 plays a key role as an inflammatory mediator and a non-invasive biomarker of non-alcoholic steatohepatitis. Journal of hepatology 2014; 61 (06) 1365-1375
    CrossrefPubMedSearch in Google Scholar
  • 23 Fan Y, Zhang W, Wei H. et al. Hepatic NK cells attenuate fibrosis progression of non-alcoholic steatohepatitis in dependent of CXCL10-mediated recruitment. Liver International 2020; 40 (03) 598-608
    CrossrefPubMedSearch in Google Scholar
  • 24 Stiglund N, Strand K, Cornillet M. et al. Retained NK Cell Phenotype and Functionality in Non-alcoholic Fatty Liver Disease. Front Immunol 2019; 10: 1255
    CrossrefPubMedSearch in Google Scholar
  • 25 Cuff AO, Sillito F, Dertschnig S. et al. The Obese Liver Environment Mediates Conversion of NK Cells to a Less Cytotoxic ILC1-Like Phenotype. Front Immunol 2019; 10: 2180
    CrossrefPubMedSearch in Google Scholar
  • 26 Gao Y, Souza-Fonseca-Guimaraes F, Bald T. et al. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nature immunology 2017; 18 (09) 1004-1015
    CrossrefPubMedSearch in Google Scholar
  • 27 Heinrich B, Gertz EM, Schäffer AA. et al. The tumour microenvironment shapes innate lymphoid cells in patients with hepatocellular carcinoma. Gut 2022; 71 (06) 1161-1175
    CrossrefPubMedSearch in Google Scholar
  • 28 McHedlidze T, Waldner M, Zopf S. et al. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity 2013; 39 (02) 357-371
    CrossrefPubMedSearch in Google Scholar
  • 29 Forkel M, Berglin L, Kekalainen E. et al. Composition and functionality of the intrahepatic innate lymphoid cell-compartment in human nonfibrotic and fibrotic livers. European journal of immunology 2017; 47 (08) 1280-1294
    CrossrefPubMedSearch in Google Scholar
  • 30 Wang S, Li J, Wu S. et al. Type 3 innate lymphoid cell: a new player in liver fibrosis progression. Clinical science (London, England : 1979) 2018; 132 (24) 2565-2582
    CrossrefPubMedSearch in Google Scholar
  • 31 Hamaguchi M, Okamura T, Fukuda T. et al. Group 3 Innate Lymphoid Cells Protect Steatohepatitis From High-Fat Diet Induced Toxicity. Front Immunol 2021; 12: 648754
    CrossrefPubMedSearch in Google Scholar
  • 32 O’Sullivan TE, Rapp M, Fan X. et al. Adipose-Resident Group 1 Innate Lymphoid Cells Promote Obesity-Associated Insulin Resistance. Immunity 2016; 45 (02) 428-441
    CrossrefPubMedSearch in Google Scholar
  • 33 Wang X, Ota N, Manzanillo P. et al. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature 2014; 514: 237-241
    CrossrefPubMedSearch in Google Scholar
  • 34 Tran S, Baba I, Poupel L. et al. Impaired Kupffer Cell Self-Renewal Alters the Liver Response to Lipid Overload during Non-alcoholic Steatohepatitis. Immunity 2020; 53 (03) 627-640.e5
    CrossrefPubMedSearch in Google Scholar
  • 35 Obstfeld AE, Sugaru E, Thearle M. et al. C-C chemokine receptor 2 (CCR2) regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis. Diabetes 2010; 59 (04) 916-925
    CrossrefPubMedSearch in Google Scholar
  • 36 Kruger AJ, Fuchs BC, Masia R. et al. Prolonged cenicriviroc therapy reduces hepatic fibrosis despite steatohepatitis in a diet-induced mouse model of nonalcoholic steatohepatitis. Hepatol Commun 2018; 2 (05) 529-545
    CrossrefPubMedSearch in Google Scholar
  • 37 Lefebvre E, Moyle G, Reshef R. et al. Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis. PloS one 2016; 11 (06) e0158156
    CrossrefPubMedSearch in Google Scholar
  • 38 Malehmir M, Pfister D, Gallage S. et al. Platelet GPIbalpha is a mediator and potential interventional target for NASH and subsequent liver cancer. Nature medicine 2019; 25 (04) 641-655
    CrossrefPubMedSearch in Google Scholar
  • 39 Ma C, Fu Q, Diggs LP. et al. Platelets control liver tumor growth through P2Y12-dependent CD40L release in NAFLD. Cancer cell 2022; 40 (09) 986-998.e5
    CrossrefPubMedSearch in Google Scholar
  • 40 Hwang S, Yun H, Moon S. et al. Role of Neutrophils in the Pathogenesis of Nonalcoholic Steatohepatitis. Front Endocrinol (Lausanne) 2021; 12: 751802
    CrossrefPubMedSearch in Google Scholar
  • 41 van der Windt DJ, Sud V, Zhang H. et al. Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis. Hepatology (Baltimore, Md) 2018; 68 (04) 1347-1360
    CrossrefPubMedSearch in Google Scholar
  • 42 Hwang S, He Y, Xiang X. et al. Interleukin-22 Ameliorates Neutrophil-Driven Nonalcoholic Steatohepatitis Through Multiple Targets. Hepatology (Baltimore, Md) 2020; 72 (02) 412-429
    CrossrefPubMedSearch in Google Scholar
  • 43 Deczkowska A, David E, Ramadori P. et al. XCR1(+) type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis. Nature medicine 2021; 27 (06) 1043-1054
    CrossrefPubMedSearch in Google Scholar
  • 44 Henning JR, Graffeo CS, Rehman A. et al. Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice. Hepatology (Baltimore, Md) 2013; 58 (02) 589-602
    CrossrefPubMedSearch in Google Scholar
  • 45 Heier EC, Meier A, Julich-Haertel H. et al. Murine CD103(+) dendritic cells protect against steatosis progression towards steatohepatitis. Journal of hepatology 2017; 66 (06) 1241-1250
    CrossrefPubMedSearch in Google Scholar
  • 46 Inada Y, Mizukoshi E, Seike T. et al. Characteristics of Immune Response to Tumor-Associated Antigens and Immune Cell Profile in Patients With Hepatocellular Carcinoma. Hepatology (Baltimore, Md) 2019; 69 (02) 653-665
    CrossrefPubMedSearch in Google Scholar
  • 47 Sutti S, Albano E. Adaptive immunity: an emerging player in the progression of NAFLD. Nature Reviews Gastroenterology & Hepatology 2020; 17 (02) 81-92
    CrossrefPubMedSearch in Google Scholar
  • 48 Zheng M, Tian Z. Liver-Mediated Adaptive Immune Tolerance. Front Immunol 2019; 10: 2525
    CrossrefPubMedSearch in Google Scholar
  • 49 Wolchok JD. Checkpoint blockade: the end of the beginning. Nature Reviews Immunology 2021; 21 (10) 621
    CrossrefPubMedSearch in Google Scholar
  • 50 Brown ZJ, Fu Q, Ma C. et al. Carnitine palmitoyltransferase gene upregulation by linoleic acid induces CD4(+) T cell apoptosis promoting HCC development. Cell Death Dis 2018; 9 (06) 620
    CrossrefPubMedSearch in Google Scholar
  • 51 Pfister D, Núñez NG, Pinyol R. et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 2021; 592: 450-456
    CrossrefPubMedSearch in Google Scholar
  • 52 Finn RS, Qin S, Ikeda M. et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. New England Journal of Medicine 2020; 382 (20) 1894-1905
    Search in Google Scholar
  • 53 Kelley RK, Greten TF. Hepatocellular Carcinoma – Origins and Outcomes. The New England journal of medicine 2021; 385 (03) 280-282
    CrossrefPubMedSearch in Google Scholar
  • 54 Abou-Alfa GK, Chan SL, Kudo M. et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. Journal of Clinical Oncology 2022; 40 (Suppl. 04) 379
    CrossrefPubMedSearch in Google Scholar
  • 55 Wang Z, Aguilar EG, Luna JI. et al. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nature medicine 2019; 25 (01) 141-151
    CrossrefPubMedSearch in Google Scholar
  • 56 Pellicci DG, Koay HF, Berzins SP. Thymic development of unconventional T cells: how NKT cells, MAIT cells and γδ T cells emerge. Nature reviews Immunology 2020; 20 (12) 756-770
    CrossrefPubMedSearch in Google Scholar
  • 57 Wolf MJ, Adili A, Piotrowitz 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 (04) 549-564
    CrossrefPubMedSearch in Google Scholar
  • 58 Lee YJ, Holzapfel KL, Zhu J. et al. Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells. Nature immunology 2013; 14 (11) 1146-1154
    CrossrefPubMedSearch in Google Scholar
  • 59 Syn WK, Agboola KM, Swiderska M. et al. NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut 2012; 61 (09) 1323-1329
    CrossrefPubMedSearch in Google Scholar
  • 60 Ma C, Han M, Heinrich B. et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science (New York, NY) 2018; 360: eaan5931
    CrossrefPubMedSearch in Google Scholar
  • 61 Toubal A, Kiaf B, Beaudoin L. et al. Mucosal-associated invariant T cells promote inflammation and intestinal dysbiosis leading to metabolic dysfunction during obesity. Nat Commun 2020; 11 (01) 3755
    CrossrefPubMedSearch in Google Scholar
  • 62 Li Y, Huang B, Jiang X. et al. Mucosal-Associated Invariant T Cells Improve Nonalcoholic Fatty Liver Disease Through Regulating Macrophage Polarization. Front Immunol 2018; 9: 1994
    CrossrefPubMedSearch in Google Scholar
  • 63 Shalapour S, Lin XJ, Bastian IN. et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 2017; 551: 340-345
    CrossrefPubMedSearch in Google Scholar
  • 64 Barrow F, Khan S, Fredrickson G. et al. Microbiota-Driven Activation of Intrahepatic B Cells Aggravates NASH Through Innate and Adaptive Signaling. Hepatology (Baltimore, Md) 2021; 74 (02) 704-722
    CrossrefPubMedSearch in Google Scholar
  • 65 Gregory SN, Perati SR, Brown ZJ. Alteration in immune function in patients with fatty liver disease. Hepatoma Research 2022; 8: 31
    CrossrefPubMedSearch in Google Scholar
  • 66 Meli R, Mattace Raso G, Calignano A. Role of innate immune response in non-alcoholic Fatty liver disease: metabolic complications and therapeutic tools. Front Immunol 2014; 5: 177
    CrossrefPubMedSearch in Google Scholar