Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling.
Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling.
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DOI：
10.1016/j.jhep.2023.04.037
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发表时间：
2023-08
影响因子：
25.7
通讯作者：
Heikenwalder, Mathias
中科院分区：
文献类型：
--
作者：
Kotsiliti, Elena;Leone, Valentina;Schuehle, Svenja;Govaere, Olivier;Li, Hai;Wolf, Monika J.;Horvatic, Helena;Bierwirth, Sandra;Hundertmark, Jana;Inverso, Donato;Zizmare, Laimdota;Sarusi-Portuguez, Avital;Gupta, Revant;O'Connor, Tracy;Giannou, Anastasios D.;Shiri, Ahmad Mustafa;Schlesinger, Yehuda;Beccaria, Maria Garcia;Rennert, Charlotte;Pfister, Dominik;Oellinger, Rupert;Gadjalova, Iana;Ramadori, Pierluigi;Rahbari, Mohammad;Rahbari, Nuh;Healy, Marc E.;Fernandez-Vaquero, Mirian;Yahoo, Neda;Janzen, Jakob;Singh, Indrabahadur;Fan, Chaofan;Liu, Xinyuan;Rau, Monika;Feuchtenberger, Martin;Schwaneck, Eva;Wallace, Sebastian J.;Cockell, Simon;Wilson-Kanamori, John;Ramachandran, Prakash;Kho, Celia;Kendall, Timothy J.;Leblond, Anne-Laure;Keppler, Selina J.;Bielecki, Piotr;Steiger, Katja;Hofmann, Maike;Rippe, Karsten;Zitzelsberger, Horst;Weber, Achim;Malek, Nisar;Luedde, Tom;Vucur, Mihael;Augustin, Hellmut G.;Flavell, Richard;Parnas, Oren;Rad, Roland;Pabst, Olivier;Henderson, Neil C.;Huber, Samuel;Macpherson, Andrew;Knolle, Percy;Claassen, Manfred;Geier, Andreas;Trautwein, Christoph;Unger, Kristian;Elinav, Eran;Waisman, Ari;Abdullah, Zeinab;Haller, Dirk;Tacke, Frank;Anstee, Quentin M.;Heikenwalder, Mathias
非酒精性脂肪性肝炎（NASH）向纤维化和肝细胞癌（HCC）的进展被自身侵袭性T细胞加重。肠-肝轴有助于NASH，但涉及的机制和NASH诱导的纤维化和肝癌的后果仍然未知。我们研究了胃肠B细胞在NASH、纤维化和NASH诱导的HCC发展中的作用。将C57 BL/6 J野生型（WT）、B细胞缺陷型和不同免疫球蛋白缺陷型或转基因小鼠饲喂不同的NASH诱导饮食或标准食物6或12个月，然后评估和分析NASH、纤维化和NASH诱导的HCC。对无特定病原体/无菌WT和μMT小鼠（仅在胃肠道中含有B细胞）喂食胆碱缺乏的高脂肪饮食，并用抗CD 20抗体治疗，然后评估NASH和纤维化。对来自单纯性脂肪变性、NASH和肝硬化患者的组织活检样品进行分析，以将免疫球蛋白的分泌与临床病理特征相关联。在小鼠和人的肝脏和胃肠道组织中进行流式细胞术、免疫组织化学和单细胞RNA测序分析，以检测免疫细胞。在小鼠和人NASH样品中，活化的肠B细胞增加，并且允许代谢T细胞活化以独立于抗原特异性和肠道微生物群诱导NASH。全身或胃肠道B细胞的遗传或治疗性耗竭预防或逆转NASH和肝纤维化。伊加分泌是通过IgA-FcR信号传导轴激活CD 11b + CCR 2 +F4/80+ CD 11 c-FCGR 1+肝髓样细胞诱导纤维化所必需的。同样，NASH患者的活化肠B细胞数量增加;此外，我们观察到伊加水平与活化FcRg+肝髓样细胞以及肝纤维化程度呈正相关。肠B细胞和IgA-FcR信号传导轴代表了治疗NASH的潜在治疗靶点。目前没有有效的治疗非酒精性脂肪性肝炎（NASH），这与大量的医疗保健负担有关，是肝细胞癌（HCC）的一个日益增长的风险因素。我们之前已经证明NASH是一种自身攻击性疾病，尤其是由T细胞加重。因此，我们假设B细胞可能在疾病的诱导和进展中发挥作用。我们目前的工作强调了B细胞在NASH发病机制中具有双重作用，涉及自身攻击性T细胞的活化和通过分泌的免疫球蛋白（例如，伊加）。此外，我们发现，缺乏B细胞阻止肝癌的发展。B细胞内在信号传导途径、分泌的免疫球蛋白以及B细胞与其他免疫细胞的相互作用是针对炎症和纤维化的组合NASH疗法的潜在靶标。肠B细胞在NASH小鼠模型中代谢活化，并且在鼠和人NASH中增加。NASH肠B细胞独立于肠道微生物群被激活。B细胞独立于TCR信号传导促进胃肠道中的代谢性T细胞活化。MoMF/SAMacs上的伊加分泌和FcRγ信号传导加剧了小鼠和NASH患者的肝纤维化。遗传和治疗性B细胞消除减少了NASH中T细胞驱动的炎症和纤维化。
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. 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 μMT 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. 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. Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for the treatment of NASH. There is currently no effective treatment for non-alcoholic steatohepatitis (NASH), which is associated with a substantial healthcare burden and is a growing risk factor for hepatocellular carcinoma (HCC). 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 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 for combinatorial NASH therapies against inflammation and fibrosis. Intestinal B cells are metabolically activated in NASH mouse models, and increased in murine and human NASH. NASH intestinal B cells are activated independently of the gut microbiota. B cells promote metabolic T-cell activation in the gastrointestinal tract independently of TCR signalling. IgA secretion and FcRγ signalling on MoMFs/SAMacs aggravate hepatic fibrosis in mice and patients with NASH. Genetic and therapeutic B-cell abrogation reduced T-cell-driven inflammation and fibrosis in NASH.
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影响因子：
4.4
作者：
CHEN, JZ;TROUNSTINE, M;HUSZAR, D
通讯作者：
HUSZAR, D
DOI：
10.1111/liv.14696
发表时间：
2020-12
期刊：
Liver international : official journal of the International Association for the Study of the Liver
影响因子：
--
作者：
De Munck TJI;Xu P;Verwijs HJA;Masclee AAM;Jonkers D;Verbeek J;Koek GH
通讯作者：
Koek GH
影响因子：
29.4
作者：
Bouter, Kristien E.;van Raalte, Daniel H.;Nieuwdorp, Max
通讯作者：
Nieuwdorp, Max
DOI：
10.1002/hep.29477
发表时间：
2018-05
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Friedman SL;Ratziu V;Harrison SA;Abdelmalek MF;Aithal GP;Caballeria J;Francque S;Farrell G;Kowdley KV;Craxi A;Simon K;Fischer L;Melchor-Khan L;Vest J;Wiens BL;Vig P;Seyedkazemi S;Goodman Z;Wong VW;Loomba R;Tacke F;Sanyal A;Lefebvre E
通讯作者：
Lefebvre E
影响因子：
64.8
作者：
Dudek, Michael;Pfister, Dominik;Knolle, Percy A.
通讯作者：
Knolle, Percy A.