Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis

IF 17.6 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2024-05-03 DOI:10.1126/sciimmunol.adk0865

Rui Li, Yanting Lei, Ayman Rezk, Diego A. Espinoza, Jing Wang, Huiru Feng, Bo Zhang, Isabella P. Barcelos, Hang Zhang, Jing Yu, Xinrui Huo, Fangyi Zhu, Changxin Yang, Hao Tang, Amy C. Goldstein, Brenda L. Banwell, Hakon Hakonarson, Hongwei Xu, Michael Mingueneau, Bo Sun, Hulun Li, Amit Bar-Or

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Abstract

Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF–expressing) and anti-inflammatory (IL-10–expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a “fourth signal” that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.

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氧化磷酸化调节 B 细胞效应细胞因子并促进多发性硬化症的炎症反应

B 细胞细胞因子分泌失调是包括多发性硬化症（MS）在内的免疫介导疾病的发病机制之一；然而，人们对其潜在机制却知之甚少。在这项研究中，我们调查了促炎性（表达 GM-CSF）和抗炎性（表达 IL-10）B 细胞分泌细胞因子的调节方式。与抗炎 B 细胞相比，促炎性人类 B 细胞需要增加氧化磷酸化（OXPHOS）。OXPHOS 通过调节三磷酸腺苷（ATP）信号传导相互调节促炎和抗炎 B 细胞的细胞因子。部分抑制 OXPHOS 或 ATP 信号转导（包括抑制 BTK）可导致抗炎性 B 细胞细胞因子的转变，逆转多发性硬化症患者体内 B 细胞细胞因子的失衡，并改善髓鞘少突胶质细胞糖蛋白（MOG）诱导的实验性自身免疫性脑炎小鼠模型的神经炎症。我们的研究确定了促炎细胞因子和抗炎细胞因子如何在 B 细胞中进行代谢调节，并确定 ATP 及其代谢产物是影响 B 细胞反应的 "第四信号"，是恢复自身免疫性疾病中 B 细胞细胞因子平衡的潜在靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.

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