Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis
Rui Li, Yanting Lei, Ayman Rezk, Diego A. Espinoza, Jing Wang, Huiru Feng, Bo Zhang, Isabella Peixoto de Barcelos, Hang Zhang, Jing Yu, Xinrui Huo, Fangyi Zhu, Changxin Yang, Hao Tang, Amy Goldstein, Brenda Banwell, Håkon Håkonarson, Hongwei Xu, Michaël Mingueneau, Bo Sun, Hulun Li, Amit Bar‐Or
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.