Lymphocytes infiltrate the stroke core and penumbra and often exacerbate cellular injury. B cells, however, are lymphocytes that do not contribute to acute pathology but can support recovery. B cell adoptive transfer to mice reduced infarct volumes 3 and 7 d after transient middle cerebral artery occlusion (tMCAo), independent of changing immune populations in recipient mice. Testing a direct neurotrophic effect, B cells cocultured with mixed cortical cells protected neurons and maintained dendritic arborization after oxygen-glucose deprivation. Whole-brain volumetric serial two-photon tomography (STPT) and a custom-developed image analysis pipeline visualized and quantified poststroke B cell diapedesis throughout the brain, including remote areas supporting functional recovery. Stroke induced significant bilateral B cell diapedesis into remote brain regions regulating motor and cognitive functions and neurogenesis (e.g., dentate gyrus, hypothalamus, olfactory areas, cerebellum) in the whole-brain datasets. To confirm a mechanistic role for B cells in functional recovery, rituximab was given to human CD20+ (hCD20+) transgenic mice to continuously deplete hCD20+-expressing B cells following tMCAo. These mice experienced delayed motor recovery, impaired spatial memory, and increased anxiety through 8 wk poststroke compared to wild type (WT) littermates also receiving rituximab. B cell depletion reduced stroke-induced hippocampal neurogenesis and cell survival. Thus, B cell diapedesis occurred in areas remote to the infarct that mediated motor and cognitive recovery. Understanding the role of B cells in neuronal health and disease-based plasticity is critical for developing effective immune-based therapies for protection against diseases that involve recruitment of peripheral immune cells into the injured brain.
Digital Object Identifier (DOI)
This study was funded by grants to A.M.S. from the American Heart Association (14SDG18410020), NIH/NINDS (NS088555), the Dana Foundation David Mahoney Neuroimaging Program, and The Haggerty Center for Brain Injury and Repair (UTSW); to S.B.O. from the American Heart Association (14POST20480373) and NIH/NINDS (3R01NS088555-03S1); to V.O.T. from the NIH/NIAID (5T32AI005284-40) and NIH/NINDS (3R01NS088555-02S1); to U.M.S. from the American Heart Association (17PRE33660147); and to A.J.E. from the NIH (DA023701, DA023555, MH107945) and the US National Aeronautics and Space Administration (NNX15AE09G). S.E.L. and C.W.W. were funded by an NIH institutional training grant (DA007290, Basic Science Training Program in the Drug Abuse Research, Principal Investigator A.J.E.).
Data deposition: All raw data have been uploaded to Harvard Dataverse, https://doi.org/10.7910/DVN/RFGT4S.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1913292117/-/DCSupplemental. The information is also available as the additional file listed at the end of this record.
Ortega, Sterling B.; Torres, Vanessa O.; Latchney, Sarah E.; Whoolery, Cody W.; Noorbhai, Ibrahim Z.; Poinsatte, Katie; Selvaraj, Uma M.; Benson, Monica A.; Meeuwissen, Anouk J. M.; Plautz, Erik J.; Kong, Xiangmei; Ramirez, Denise M.; Ajay, Apoorva D.; Meeks, Julian P.; Goldberg, Mark P.; Monson, Nancy L.; Eisch, Amelia J.; and Stowe, Ann M., "B Cells Migrate into Remote Brain Areas and Support Neurogenesis and Functional Recovery after Focal Stroke in Mice" (2020). Neurology Faculty Publications. 34.