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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Microbiota-Driven Activation of Intrahepatic B Cells Aggravates NASH Through Innate and Adaptive Signaling
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Microbiota-Driven Activation of Intrahepatic B Cells Aggravates NASH Through Innate and Adaptive Signaling

机译：微生物群驱动的肝内 B 细胞活化通过先天性和适应性信号转导加重 NASH

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BACKGROUND AND AIMS: 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. APPROACH AND RESULTS: In this study, we report that NASH livers accumulate B cells with elevated proinflammatory 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 NASI I 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 NASI I by increasing the accumulation and activation of intrahepatic B cells, suggesting that gut microbial factors drive the pathogenic function of B cells during NASH. CONCLUSION: 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.
机译：背景和目的：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适应症。肝脏炎症是NASH的一个关键特征，但对这一过程中涉及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，是免疫反应的关键调节因子。然而，B细胞在NASH发病机制中的作用以及导致其在肝脏中激活的潜在机制尚不清楚。方法和结果：在这项研究中，我们报告了NASH肝脏积累的B细胞具有升高的促炎细胞因子分泌和抗原呈递能力。对NASH小鼠肝内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 NASI I 肝脏过继转移 B 细胞可以概括该疾病。从机制上讲，NASH 期间的 B 细胞活化涉及通过先天衔接子髓样分化初级反应蛋白 88 （MyD88） 进行信号传导，因为 MyD88 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 细胞的激活涉及 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肠道微生物群移植到受体小鼠体内的粪便微生物群通过增加肝内B细胞的积累和活化来促进NASI I的进展，表明肠道微生物因子驱动NASH期间B细胞的致病功能。结论：我们的研究结果表明，肠道微生物群驱动的肝内B细胞激活通过先天性和适应性免疫机制在NASH进展过程中导致肝脏炎症和纤维化。

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