B cells upregulate NMDARs, respond to extracellular glutamate, and express mature BDNF to protect the brain from ischemic injury.

Abstract

Following stroke, B cells enter brain regions outside of the ischemic injury to mediate functional recovery. Although B cells produce neurotrophins that support remote plasticity, including brain-derived neurotrophic factor (BDNF), it remains unclear which signal(s) activate B cells in the absence of infarct-localized pro-inflammatory cues. Activation of N-methyl-d-aspartate (NMDA)-type receptor (NMDAR) subunits on neurons can upregulate mature BDNF (mBDNF) production from a pro-BDNF precursor, but whether this occurs in B cells is unknown. We identified GluN2A and GluN2B NMDAR subunits on B cells that respond to glutamate and mediate nearly half of the glutamate-induced Ca²⁺ responses in activated B cell subsets. Ischemic stroke recruits GluN2A⁺ B cells into the ipsilesional hemisphere and both stroke and neurophysiologic levels of glutamate regulate gene and surface expression. Regardless of injury, pro-BDNF⁺ B localize to spleen/circulation whereas mBDNF⁺ B cells localize to the brain, including in aged male and female mice. We confirmed B cell-derived BDNF was required for in vitro and in vivo B cell-mediated neuroprotection. Lastly, GluN2A, GluN2B, glutamate-induced Ca²⁺ responses, and BDNF expression were all clinically confirmed in B cells from healthy donors, with BDNF⁺ B cells present in post-stroke human parenchyma. These data suggest that B cells express functional NMDARs that respond to glutamate, enhance NMDAR signaling with activation, and upregulate mature BDNF expression within the brain. This study identifies potential glutamate-induced neurotrophic roles for B cells in the brain; an immune response to neurotransmitters unique from established pro-inflammatory stimuli and relevant to any CNS-localized injury or disease.