Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling

被引：46

作者：

Kotsiliti, Elena ^{[1
]}

Leone, Valentina ^{[1
,2
,3
,45
]}

Schuehle, Svenja ^{[1
,43
]}

Govaere, Olivier ^{[4
]}

Li, Hai ^{[5
]}

Wolf, Monika J. ^{[48
]}

Horvatic, Helena ^{[6
]}

Bierwirth, Sandra ^{[7
,8
]}

Hundertmark, Jana ^{[9
,10
]}

Inverso, Donato ^{[11
,12
]}

Zizmare, Laimdota ^{[13
]}

Sarusi-Portuguez, Avital ^{[14
]}

Gupta, Revant ^{[15
,16
]}

O'Connor, Tracy ^{[1
,44
]}

Giannou, Anastasios D. ^{[17
,18
]}

Shiri, Ahmad Mustafa ^{[17
]}

Schlesinger, Yehuda ^{[14
]}

Beccaria, Maria Garcia ^{[1
]}

Rennert, Charlotte ^{[18
]}

Pfister, Dominik ^{[1
]}

Oellinger, Rupert ^{[3
]}

Gadjalova, Iana ^{[19
]}

Ramadori, Pierluigi ^{[1
]}

Rahbari, Mohammad ^{[1
]}

Rahbari, Nuh ^{[20
]}

Healy, Marc E. ^{[22
]}

Fernandez-Vaquero, Mirian ^{[1
]}

Yahoo, Neda ^{[1
]}

Janzen, Jakob ^{[1
]}

Singh, Indrabahadur ^{[1
,41
]}

Fan, Chaofan ^{[1
]}

Liu, Xinyuan ^{[21
,22
]}

Rau, Monika ^{[23
]}

Feuchtenberger, Martin ^{[24
]}

Schwaneck, Eva ^{[25
]}

Wallace, Sebastian J. ^{[26
]}

Cockell, Simon ^{[42
]}

Wilson-Kanamori, John ^{[26
]}

Ramachandran, Prakash ^{[26
]}

Kho, Celia ^{[6
]}

Kendall, Timothy J. ^{[26
,27
]}

Leblond, Anne-Laure ^{[32
,33
]}

Keppler, Selina J. ^{[19
]}

Bielecki, Piotr ^{[28
]}

Steiger, Katja ^{[29
,30
]}

Hofmann, Maike ^{[15
]}

Rippe, Karsten ^{[31
]}

Zitzelsberger, Horst ^{[2
]}

Weber, Achim ^{[32
,33
]}

Malek, Nisar ^{[34
]}

机构：

[1] German Canc Res Ctr Heidelberg DKFZ, Div Chron Inflammat & Canc, Heidelberg, Germany

[2] Helmholtz Zentrum Munchen, Res Unit Radiat Cytogenet ZYTO, Neuherberg, Germany

[3] Tech Univ Munich TUM, Inst Mol Oncol & Funct Genom, Clin & Polyclin Internal Med 2, Klinikum rechts Isar, Munich, Germany

[4] Newcastle Univ, Translat & Clin Res Inst, Fac Med Sci, Newcastle Upon Tyne, England

[5] Univ Bern, Univ Dept Visceral Surg & Med Inselspital, Maurice Muller Labs DBMR, Bern, Switzerland

[6] Univ Hosp, Inst Mol Med & Expt Immunol, Bonn, Germany

[7] Tech Univ Munich, Nutr & Immunol, Freising Weihenstephan, Germany

[8] Tech Univ Munich, ZIEL Inst Food & Hlth, Freising Weihenstephan, Germany

[9] Charite Univ Med Berlin, Dept Hepatol & Gastroenterol, Campus Virchow Klinikum, Berlin, Germany

[10] Campus Charite Mitte, Berlin, Germany

[11] German Canc Res Ctr Heidelberg DKFZ ZMBH Alliance, Div Vasc Oncol & Metastasis, Heidelberg, Germany

[12] Heidelberg Univ, Med Fac Mannheim, European Ctr Angioscience ECAS, Mannheim, Germany

[13] Tubingen Univ, Werner Siemens Imaging Ctr WS, Dept Preclin Imaging & Radiopharm, Tubingen, Germany

[14] Hebrew Univ Hadassah Med Sch, Concern Fdn Labs, Lautenberg Ctr Immunol & Canc Res, IMRIC,Fac Med, Jerusalem, Israel

[15] Univ Tubingen, Univ Hosp Tubingen, Fac Med, Internal Med 1, Tubingen, Germany

[16] Univ Tubingen, Dept Comp Sci, Tubingen, Germany

[17] Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Sect Mol Immunol & Gastroenterol, Hamburg, Germany

[18] Univ Freiburg, Univ Hosp Freiburg, Fac Med, Dept Med 2, Freiburg, Germany

[19] Tech Univ Munich TUM, Ctr Translat Canc Res TranslaTUM, Munich, Germany

[20] Heidelberg Univ, Dept Gen Visceral & Transplantat Surg, Heidelberg, Germany

[21] Johannes Gutenberg Univ Mainz, Res Ctr Immunotherapy FZI, Univ Med Ctr, Mainz, Germany

[22] Johannes Gutenberg Univ Mainz, Inst Mol Med, Univ Med Ctr, Mainz, Germany

[23] Univ Hosp Wurzburg, Div Hepatol, Wurzburg, Germany

[24] Kreiskliniken Altotting Burghausen, Rheumatol Clin Immunol, Burghausen, Germany

[25] Julius Maximilians Univ Wurzburg, Med Clin 2, Rheumatol, Wurzburg, Germany

[26] Univ Edinburgh, Queens Med Res Inst, Ctr Inflammat Res, Edinburgh, Scotland

[27] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Scotland

[28] Yale Univ, Dept Immunobiol, Sch Med, New Haven, CT USA

[29] Tech Univ Munich TUM, Inst Pathol, Munich, Germany

[30] Tech Univ Munich TUM, Comparat Expt Pathol, Munich, Germany

[31] German Canc Res Ctr DKFZ & Bioquant, Div Chromatin Networks, Heidelberg, Germany

[32] Univ Zurich, Dept Pathol & Mol Pathol, Zurich, Switzerland

[33] Univ Hosp Zurich, Zurich, Switzerland

[34] Eberhard Karls Univ Tubingen, Dept Internal Med 1, Tubingen, Germany

[35] Heinrich Heine Univ, Univ Hosp Duesseldorf, Dept Gastroenterol Hepatol & Infect Dis, Med Fac, Dusseldorf, Germany

[36] Rhein Westfal TH Aachen, Inst Mol Med, Aachen, Germany

[37] Tech Univ Munich, Inst Mol Immunol & Expt Oncol, Klinikum rechts Isar, Munich, Germany

[38] Weizmann Inst Sci, Immunol Dept, Rehovot, Israel

[39] DKFZ, Canc Microbiome Res Div, Heidelberg, Germany

[40] Newcastle Tyne Hosp NHS Trust, Newcastle NIHR Biomed Res Ctr, Newcastle Upon Tyne, England

[41] German Canc Res Ctr, Div Chron Inflammat & Canc, Emmy Noether Res Grp Epigenet Machineries & Canc, Heidelberg, Germany

[42] Newcastle Univ, Fac Med Sci, Sch Biomed Nutr & Sports Sci, Newcastle Upon Tyne, England

[43] Heidelberg Univ, Fac Biosci, Heidelberg, Germany

[44] North Pk Univ, Chicago, IL USA

[45] Tech Univ Munich TUM, Translat Pancreat Canc Res Ctr, Clin & Polyclin Internal Med 2, Klinikum Rechts Isar, Munich, Germany

[46] Eberhard Karls Univ Tubingen, Res Inst M3, Tubingen, Germany

[47] German Canc Res Ctr, Dept Chron Inflammat & Canc, Neuenheimer Feld 242, D-69120 Heidelberg, Germany

[48] Roche Innovat Ctr Munich, Roche Pharmaceut Res & Early Dev Oncol, Penzberg, Germany

来源：

JOURNAL OF HEPATOLOGY | 2023年 / 79卷 / 02期

基金：

欧洲研究理事会; 英国惠康基金; 欧盟地平线“2020”;

关键词：

NAFLD; NAFL; NASH; HCC; fibrosis; B cells; gut-liver axis; FATTY LIVER-DISEASE; DIET-INDUCED OBESITY; NONALCOHOLIC STEATOHEPATITIS; TARGETED DELETION; IMMUNOGLOBULIN-A; MOUSE MODEL; MICE; PROMOTES; CANCER; SYK;

D O I：

10.1016/j.jhep.2023.04.037

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background & Aims: The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC. Methods: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH-inducing diets or standard chow for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and lMT mice (containing B cells only in the gastrointestinal tract) were fed a choline-deficient high-fat diet, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with simple steatosis, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and single-cell RNA-sequencing analysis were performed in liver and gastrointestinal tissue to characterise immune cells in mice and humans. Results: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B cells; additionally, we observed a positive correlation between IgA levels and activated FcRg+ hepatic myeloid cells, as well the extent of liver fibrosis. Conclusions: Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for the treatment of NASH.& COPY; 2023 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

引用

页码：296 / +

页数：19