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.

中文翻译：

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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中的炎症

B 细胞细胞因子产生失调会导致免疫介导疾病的发病，包括多发性硬化症 (MS)；然而，人们对其基本机制知之甚少。在这项研究中，我们研究了促炎（表达 GM-CSF）和抗炎（表达 IL-10）B 细胞的细胞因子分泌是如何受到调节的。与抗炎 B 细胞相比，促炎人类 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 细胞细胞因子。部分抑制 OXPHOS 或 ATP 信号传导（包括 BTK 抑制）可导致抗炎 B 细胞细胞因子转变，逆转 MS 患者的 B 细胞细胞因子失衡，并改善髓磷脂少突胶质细胞糖蛋白 (MOG) 诱导的实验性自身免疫性脑炎的神经炎症鼠标模型。我们的研究确定了促炎和抗炎细胞因子如何在 B 细胞中进行代谢调节，并将 ATP 及其代谢物确定为塑造 B 细胞反应的“第四信号”，并且是恢复自身免疫性疾病中 B 细胞细胞因子平衡的潜在目标。