Microbiota-Driven Activation of Intrahepatic B Cells Aggravates NASH Through Innate and Adaptive Signaling.
Microbiota-Driven Activation of Intrahepatic B Cells Aggravates NASH Through Innate and Adaptive Signaling.
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DOI：
10.1002/hep.31755
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Revelo XS
中科院分区：
文献类型：
--
作者：
Barrow F;Khan S;Fredrickson G;Wang H;Dietsche K;Parthiban P;Robert S;Kaiser T;Winer S;Herman A;Adeyi O;Mouzaki M;Khoruts A;Hogquist KA;Staley C;Winer DA;Revelo XS
非酒精性脂肪性肝炎正迅速成为肝衰竭的主要原因和肝移植的指征。肝脏炎症是NASH的一个关键特征，但参与这一过程的免疫途径知之甚少。B淋巴细胞是适应性免疫系统的细胞，是免疫应答的关键调节剂。然而，B细胞在NASH发病机制中的作用以及导致其在肝脏中活化的潜在机制尚不清楚。在这项研究中，我们报告了NASH肝脏积聚的B细胞具有升高的促炎细胞因子分泌和抗原呈递能力。来自NASH小鼠的肝内B细胞的单细胞和批量RNA测序揭示了反映其促炎功能的转录景观。因此，B-细胞缺乏改善了NASH进展，并且从NASH肝脏过继转移B细胞重现了该疾病。从机制上讲，NASH期间的B-细胞活化涉及通过先天衔接髓样分化初级应答蛋白88（MyD 88）的信号传导，因为MyD 88的B细胞特异性缺失减少了肝T细胞介导的炎症和纤维化，但不减少脂肪变性。此外，肝内B细胞的活化涉及B细胞受体信号传导，描绘了抗原识别的先天性和适应性机制之间的协同作用。此外，将人NAFLD肠道微生物菌群的粪便微生物群移植到受体小鼠中通过增加肝内B细胞的积累和活化来促进NASH的进展，这表明肠道微生物因子在NASH期间驱动B细胞的致病功能。我们的研究结果表明，在NASH进展过程中，肠道微生物群驱动的肝内B细胞活化通过先天性和适应性免疫机制导致肝脏炎症和纤维化。
Nonalcoholic steatohepatitis is rapidly becoming the leading cause of liver failure and indication for liver transplantation. Hepatic inflammation is a key feature of NASH but the immune pathways involved in this process are poorly understood. B lymphocytes are cells of the adaptive immune system that are critical regulators of immune responses. However, the role of B cells in the pathogenesis of NASH and the potential mechanisms leading to their activation in the liver are unclear. In this study, we report that NASH livers accumulate B cells with elevated pro‐inflammatory cytokine secretion and antigen‐presentation ability. Single‐cell and bulk RNA sequencing of intrahepatic B cells from mice with NASH unveiled a transcriptional landscape that reflects their pro‐inflammatory function. Accordingly, B‐cell deficiency ameliorated NASH progression, and adoptively transferring B cells from NASH livers recapitulates the disease. Mechanistically, B‐cell activation during NASH involves signaling through the innate adaptor myeloid differentiation primary response protein 88 (MyD88) as B cell–specific deletion of MyD88 reduced hepatic T cell–mediated inflammation and fibrosis, but not steatosis. In addition, activation of intrahepatic B cells implicates B cell–receptor signaling, delineating a synergy between innate and adaptive mechanisms of antigen recognition. Furthermore, fecal microbiota transplantation of human NAFLD gut microbiotas into recipient mice promoted the progression of NASH by increasing the accumulation and activation of intrahepatic B cells, suggesting that gut microbial factors drive the pathogenic function of B cells during NASH. Our findings reveal that a gut microbiota–driven activation of intrahepatic B cells leads to hepatic inflammation and fibrosis during the progression of NASH through innate and adaptive immune mechanisms.
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影响因子：
7.7
作者：
Cani, Patrice D.;Amar, Jacques;Burcelin, Remy
通讯作者：
Burcelin, Remy
影响因子：
16.6
作者：
MacParland SA;Liu JC;Ma XZ;Innes BT;Bartczak AM;Gage BK;Manuel J;Khuu N;Echeverri J;Linares I;Gupta R;Cheng ML;Liu LY;Camat D;Chung SW;Seliga RK;Shao Z;Lee E;Ogawa S;Ogawa M;Wilson MD;Fish JE;Selzner M;Ghanekar A;Grant D;Greig P;Sapisochin G;Selzner N;Winegarden N;Adeyi O;Keller G;Bader GD;McGilvray ID
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McGilvray ID
影响因子：
32.4
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Hou, Baidong;Reizis, Boris;DeFranco, Anthony L.
通讯作者：
DeFranco, Anthony L.
影响因子：
32.4
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Fielding, Ceri A.;Jones, Gareth W.;McLoughlin, Rachel M.;McLeod, Louise;Hammond, Victoria J.;Uceda, Javier;Williams, Anwen S.;Lambie, Mark;Foster, Thomas L.;Liao, Chia-Te;Rice, Christopher M.;Greenhill, Claire J.;Colmont, Chantal S.;Hams, Emily;Coles, Barbara;Kift-Morgan, Ann;Newton, Zarabeth;Craig, Katherine J.;Williams, John D.;Williams, Geraint T.;Davies, Simon J.;Humphreys, Ian R.;O'Donnell, Valerie B.;Taylor, Philip R.;Jenkins, Brendan J.;Topley, Nicholas;Jones, Simon A.
通讯作者：
Jones, Simon A.
影响因子：
15.9
作者：
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通讯作者：
Mehal, Wajahat Zafar