Editor’s summary
Patients with multiple sclerosis (MS) harbor high frequencies of pro-inflammatory B cells, which promote inflammation; yet, it is unclear how cytokine production in B cells is regulated. Li et al. studied cytokine regulation in pro-inflammatory (GM-CSF+) and anti-inflammatory (IL-10+) human B cells, identifying that pro-inflammatory B cells were more metabolically active with increased oxidative phosphorylation (OXPHOS). B cells from patients with MS also had increased OXPHOS, which was required for pro-inflammatory cytokine production, and inhibition of OXPHOS or BTK restored the balance of cytokine production. B cell OXPHOS contributed to the pathogenesis of neuroinflammation in mice by regulating adenosine triphosphate (ATP) signaling. These findings indicate that human B cell cytokine production is metabolically regulated and identify OXPHOS as a potential target for the treatment of MS. —Hannah Isles
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.
