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

Authors

• Vanessa O. Torres, University of Texas Southwestern Medical Center
• Jadwiga Turchan-Cholewo, University of Kentucky College of MedicineFollow
• Mary K. Colson, University of Kentucky College of Medicine
• Pavel Yanev, University of Kentucky College of Medicine
• Daimen R.S. Britsch, University of Kentucky College of MedicineFollow
• Katherine M. Cotter, University of Kentucky College of Medicine
• Annabel M. McAtee, University of Kentucky College of Medicine
• Thomas A. Ujas, University of Kentucky College of MedicineFollow
• Domenico Mercurio, University of Kentucky College of Medicine
• Xiangmei Kong, University of Texas Southwestern Medical Center
• Erik J. Plautz, University of Texas Southwestern Medical Center
• Chaitanya R. Joshi, University of Texas Southwestern Medical Center
• Takeshi K. Matsui, Shimane University
• Eiichiro Mori, Nara Medical University
• Ambar Cajigas-Hernandez, University of Texas Southwestern Medical Center
• Kielen Zuurbier, University of Texas Southwestern Medical Center
• Steven Estus, University of KentuckyFollow
• Mark P. Goldberg, University of Texas Southwestern Medical Center
• Nancy L. Monson, University of Texas Southwestern Medical Center
• Ann M. Stowe, University of KentuckyFollow

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 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.

Document Type

Article

Publication Date

4-1-2025

Notes/Citation Information

Publisher Copyright: © 2025 The Authors

Digital Object Identifier (DOI)

10.1016/j.nbd.2025.106819

Archival?

Archival

Repository Citation

Torres, Vanessa O.; Turchan-Cholewo, Jadwiga; Colson, Mary K.; Yanev, Pavel; Britsch, Daimen R.S.; Cotter, Katherine M.; McAtee, Annabel M.; Ujas, Thomas A.; Mercurio, Domenico; Kong, Xiangmei; Plautz, Erik J.; Joshi, Chaitanya R.; Matsui, Takeshi K.; Mori, Eiichiro; Cajigas-Hernandez, Ambar; Zuurbier, Kielen; Estus, Steven; Goldberg, Mark P.; Monson, Nancy L.; and Stowe, Ann M., "B cells upregulate NMDARs, respond to extracellular glutamate, and express mature BDNF to protect the brain from ischemic injury" (2025). Physiology Faculty Publications. 256.
https://uknowledge.uky.edu/physiology_facpub/256