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

• DOI: 10.1016/j.nbd.2025.106819
• Publication Date: 2025-02-01T16:08:21Z
• Authors: Vanessa O. Torres; Jadwiga Turchan-C...; Mary K. Colson; Pavel Yanev; Daimen R.S. Britsch; Katherine M. Cotter; Annabel M. McAtee; Thomas A. Ujas; Domenico Mercurio; Xiangmei Kong; Erik J. Plautz; Chaitanya R. Joshi; Takeshi K. Matsui; Eiichiro Mori; Ambar Cajigas-Her...; Kielen Zuurbier; Steven Estus; Mark P. Goldberg; Nancy L. Monson; Ann M. Stowe
• Keywords: GluN2B; GluN2A; IL-10; Neurosciences. Biological psychiatry. Neuropsychiatry; Cerebral ischemia; Brain-derived neurotrophic factor; B lymphocytes; RC321-571

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 cells 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.