作者
Eleni Kotsiliti,Valentina Leone,Svenja Schuehle,Olivier Govaere,Hai Li,Monika Wolf,Helena Horvatic,Sandra Bierwirth,Jana Hundertmark,Donato Inverso,Laimdota Zizmare,Avital Sarusi-Portuguez,Revant Gupta,Tracy O’Connor,Anastasios D. Giannou,Ahmad Mustafa Shiri,Y. Schlesinger,María García‐Beccaria,Charlotte Rennert,Dominik Pfister,Rupert Öllinger,Iana Gadjalova,Pierluigi Ramadori,Mohammad Rahbari,Nuh N. Rahbari,Marc E. Healy,Mirian Fernández-Vaquero,Neda Yahoo,Jakob Janzen,Indrabahadur Singh,Chaofan Fan,Xinyuan Liu,Monika Rau,Hans‐Peter Tony,Eva C. Schwaneck,Sebastian Wallace,Simon Cockell,John R. Wilson‐Kanamori,Prakash Ramachandran,Celia Kho,Timothy J. Kendall,Anne-Laure Leblond,Selina J. Keppler,Piotr Bielecki,Katja Steiger,Maike Hofmann,Karsten Rippe,Horst Zitzelsberger,Achim Weber,Nisar P. Malek,Tom Luedde,Mihael Vucur,Hellmut G. Augustin,Richard A. Flavell,Oren Parnas,Roland Rad,Olivier Pabst,Neil C. Henderson,Samuel Huber,Andrew J. Macpherson,Percy A. Knolle,Manfred Claassen,Andreas Geier,Christoph Trautwein,Kristian Unger,Eran Elinav,Ari Waisman,Zeinab Abdullah,Dirk Haller,Frank Tacke,Quentin M. Anstee,Mathias Heikenwälder
摘要
Background & AimsThe progression of nonalcoholic 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.MethodsC57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH diets (for example, choline-deficient high-fat diet, CD-HFD) or chow diet for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a CD-HFD, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with NAFL, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and scRNA-Seq analysis were performed in liver and gastrointestinal tissue for immune cells in mice and humans.ResultsActivated 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 and showed a positive correlation between IgA levels and activated FcRγ+ hepatic myeloid cells as well extent of liver fibrosis.ConclusionsIntestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for treating NASH.Impact and ImplicationsNonalcoholic steatohepatitis (NASH) is a chronic inflammatory condition on the rise and can lead to hepatocellular carcinoma (HCC), the 3rd most common cause of cancer-related death worldwide. Currently, there is no effective treatment for this progressive disease that correlates with a marked risk of HCC mortality and carries a substantial healthcare burden. To date, among all the solid tumours, especially in HCC, the incidence and mortality rates are almost the same, making it crucial to find curative treatments for chronic diseases, such as NASH, which highly predispose to tumorigenesis.We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we could show that the absence of B cells prevented HCC development.B-cell intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets in combinatorial NASH therapies against inflammation and fibrosis.