B cells migrate into remote brain areas and support neurogenesis and functional recovery after focal stroke in mice
| Autor: | Amelia J. Eisch, Erik J. Plautz, Monica A. Benson, Sarah E. Latchney, Julian P. Meeks, Cody W. Whoolery, Mark P. Goldberg, Apoorva D. Ajay, Ann M. Stowe, Vanessa O. Torres, Sterling B. Ortega, Nancy L. Monson, Ibrahim Noorbhai, Uma Maheswari Selvaraj, Katie Poinsatte, Anouk Meeuwissen, Denise M.O. Ramirez, Xiangmei Kong |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Adoptive cell transfer Cerebellum Neurogenesis serial two-photon tomography Mice Transgenic Hippocampal formation Adaptive Immunity 03 medical and health sciences Mice 0302 clinical medicine Cognition Cell Movement Medicine Animals Humans B cell 030304 developmental biology Neurons 0303 health sciences B-Lymphocytes Multidisciplinary Neuronal Plasticity biology business.industry Dentate gyrus focal stroke Brain Infarction Middle Cerebral Artery Recovery of Function Biological Sciences Acquired immune system 3. Good health Mice Inbred C57BL Stroke Disease Models Animal medicine.anatomical_structure Dentate Gyrus biology.protein business Neuroscience 030217 neurology & neurosurgery Neurotrophin B lymphocytes |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance Neuroinflammation occurs immediately after stroke onset in the ischemic infarct, but whether neuroinflammation occurs in remote regions supporting plasticity and functional recovery remains unknown. We used advanced imaging to quantify whole-brain diapedesis of B cells, an immune cell capable of producing neurotrophins. We identify bilateral B cell diapedesis into remote regions, outside of the injury, that support motor and cognitive recovery in young male mice. Poststroke depletion of B cells confirms a positive role in neurogenesis, neuronal survival, and recovery of motor coordination, spatial learning, and anxiety. More than 80% of stroke survivors have long-term disability uniquely affected by age and lifestyle factors. Thus, identifying beneficial neuroinflammation during long-term recovery increases the opportunity of therapeutic interventions to support functional recovery. 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. |
| Databáze: | OpenAIRE |
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