Compartmentalized B cell-microglia crosstalk drives ischemic white matter demyelination

Abstract

Ischemic white matter injury and the consequent neuroimmune response can contribute to vascular cognitive impairment. The role of B cells in ischemic white matter injury is unclear. Here, we show that crosstalk between meningeal B cells and CNS-resident microglia exacerbates white matter injury and vascular cognitive impairment. The B cell population expands and is activated in the dura mater, correlating with worsened white matter damage and neuroinflammation, whereas B cell depletion alleviates myelin thinning and cognitive impairment following chronic cerebral hypoperfusion in adult male mice. Mechanistically, microglia recruit meningeal B cells via MIF-CD74/CXCR4 signaling, and B cells adopt an IgG-secreting phenotype. IgG-secreting B cells induce microglial ferroptosis through Fc gamma receptors. Our data show that B cells contribute to white matter injury and cognitive impairment. The role of B cells in vascular cognitive impairment is unclear. Here, the authors show a crosstalk between CNS border-associated B cells and parenchymal microglia, through MIFCD74/CXCR4 and IgG signaling, exacerbating white matter injury.