B cells migrate into remote brain areas and support neurogenesis and functional recovery after focal stroke in mice

Author:

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.ORCID,Stowe Ann M.ORCID

Abstract

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.

Funder

American Heart Association

HHS | NIH | National Institute of Neurological Disorders and Stroke

Dana Foundation

Haggerty Center for Brain Injury and Repair

HHS | NIH | National Institute of Allergy and Infectious Diseases

HHS | NIH | National Institute on Drug Abuse

HHS | NIH | National Institute of Mental Health

National Aeronautics and Space Administration

Texas Institute for Brain Injury and Repair, University of Texas Southwestern Medical Center

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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