B cells upregulate NMDARs, respond to extracellular glutamate, and express mature BDNF to protect the brain from ischemic injury
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 o...
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Elsevier
2025-04-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S096999612500035X |
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| author | Vanessa O. Torres Jadwiga Turchan-Cholewo 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-Hernandez Kielen Zuurbier Steven Estus Mark P. Goldberg Nancy L. Monson Ann M. Stowe |
| author_facet | Vanessa O. Torres Jadwiga Turchan-Cholewo 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-Hernandez Kielen Zuurbier Steven Estus Mark P. Goldberg Nancy L. Monson Ann M. Stowe |
| author_sort | Vanessa O. Torres |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-244e8f51c5a7437f93a5c97dfd23d79b |
| institution | DOAJ |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-244e8f51c5a7437f93a5c97dfd23d79b2025-08-20T02:55:46ZengElsevierNeurobiology of Disease1095-953X2025-04-0120710681910.1016/j.nbd.2025.106819B cells upregulate NMDARs, respond to extracellular glutamate, and express mature BDNF to protect the brain from ischemic injuryVanessa O. Torres0Jadwiga Turchan-Cholewo1Mary K. Colson2Pavel Yanev3Daimen R.S. Britsch4Katherine M. Cotter5Annabel M. McAtee6Thomas A. Ujas7Domenico Mercurio8Xiangmei Kong9Erik J. Plautz10Chaitanya R. Joshi11Takeshi K. Matsui12Eiichiro Mori13Ambar Cajigas-Hernandez14Kielen Zuurbier15Steven Estus16Mark P. Goldberg17Nancy L. Monson18Ann M. Stowe19Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Suite NL9.114, Dallas, TX 75390-8813, USA; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USADepartment of Neurology, University of Kentucky, 740 S. Limestone, Kentucky Clinic J-455, Lexington, KY 40536, USADepartment of Neurology, University of Kentucky, 740 S. Limestone, Kentucky Clinic J-455, Lexington, KY 40536, USADepartment of Neurology, University of Kentucky, 740 S. Limestone, Kentucky Clinic J-455, Lexington, KY 40536, USADepartment of Neurology, University of Kentucky, 740 S. Limestone, Kentucky Clinic J-455, Lexington, KY 40536, USADepartment of Neurology, University of Kentucky, 740 S. Limestone, Kentucky Clinic J-455, Lexington, KY 40536, USADepartment of Neurology, University of Kentucky, 740 S. Limestone, Kentucky Clinic J-455, Lexington, KY 40536, USADepartment of Neurology, University of Kentucky, 740 S. Limestone, Kentucky Clinic J-455, Lexington, KY 40536, USADepartment of Neurology, University of Kentucky, 740 S. Limestone, Kentucky Clinic J-455, Lexington, KY 40536, USADepartment of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Suite NL9.114, Dallas, TX 75390-8813, USADepartment of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Suite NL9.114, Dallas, TX 75390-8813, USADepartment of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Suite NL9.114, Dallas, TX 75390-8813, USADepartment of Neural and Muscular Physiology, Shimane University School of Medicine, 89-1 Enya-cho, Izumo-shi 693-8501, Shimane, Japan; Department of Future Basic Medicine, Nara Medical University, 840 Shijo-Cho, Kashihara, 634-8521 Nara, JapanDepartment of Future Basic Medicine, Nara Medical University, 840 Shijo-Cho, Kashihara, 634-8521 Nara, JapanDepartment of Neuroscience, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9111, USADepartment of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9148, USADepartment of Physiology, University of Kentucky, 741 S. Limestone, BBSRB B243, Lexington, KY 40536, USADepartment of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Suite NL9.114, Dallas, TX 75390-8813, USA; Department of Neurology, Institute for Integration of Medicine and Science, UT Health San Antonio, 7703 Floyd Curl Drive, MSC 7883, San Antonio, TX 78229, USADepartment of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Suite NL9.114, Dallas, TX 75390-8813, USA; Department of Immunology, University of Texas Southwestern Medical Center, 6124 Harry Hines Blvd., Dallas, TX 75390-9093, USADepartment of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Suite NL9.114, Dallas, TX 75390-8813, USA; Department of Neurology, University of Kentucky, 740 S. Limestone, Kentucky Clinic J-455, Lexington, KY 40536, USA; Corresponding author at: Department of Neurology, BBSRB 479, 741 S. Limestone St., Lexington, KY 40508, USA.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.http://www.sciencedirect.com/science/article/pii/S096999612500035XCerebral ischemiaB lymphocytesGluN2AGluN2BBrain-derived neurotrophic factorIL-10 |
| spellingShingle | Vanessa O. Torres Jadwiga Turchan-Cholewo 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-Hernandez Kielen Zuurbier Steven Estus Mark P. Goldberg Nancy L. Monson Ann M. Stowe B cells upregulate NMDARs, respond to extracellular glutamate, and express mature BDNF to protect the brain from ischemic injury Neurobiology of Disease Cerebral ischemia B lymphocytes GluN2A GluN2B Brain-derived neurotrophic factor IL-10 |
| title | B cells upregulate NMDARs, respond to extracellular glutamate, and express mature BDNF to protect the brain from ischemic injury |
| title_full | B cells upregulate NMDARs, respond to extracellular glutamate, and express mature BDNF to protect the brain from ischemic injury |
| title_fullStr | B cells upregulate NMDARs, respond to extracellular glutamate, and express mature BDNF to protect the brain from ischemic injury |
| title_full_unstemmed | B cells upregulate NMDARs, respond to extracellular glutamate, and express mature BDNF to protect the brain from ischemic injury |
| title_short | B cells upregulate NMDARs, respond to extracellular glutamate, and express mature BDNF to protect the brain from ischemic injury |
| title_sort | b cells upregulate nmdars respond to extracellular glutamate and express mature bdnf to protect the brain from ischemic injury |
| topic | Cerebral ischemia B lymphocytes GluN2A GluN2B Brain-derived neurotrophic factor IL-10 |
| url | http://www.sciencedirect.com/science/article/pii/S096999612500035X |
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