B cell treatment promotes a neuroprotective microenvironment after traumatic brain injury through reciprocal immunomodulation with infiltrating peripheral myeloid cells

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Abstract

Traumatic brain injury (TBI) remains a major cause of death and severe disability worldwide. We found previously that treatment with exogenous naïve B cells was associated with structural and functional neuroprotection after TBI. Here, we used a mouse model of unilateral controlled cortical contusion TBI to investigate cellular mechanisms of immunomodulation associated with intraparenchymal delivery of mature naïve B lymphocytes at the time of injury. Exogenous B cells showed a complex time-dependent response in the injury microenvironment, including significantly increased expression of IL-10, IL-35, and TGFβ, but also IL-2, IL-6, and TNFα. After 10 days in situ, B cell subsets expressing IL-10 or TGFβ dominated. Immune infiltration into the injury predominantly comprised myeloid cells, and B cell treatment did not alter overall numbers of infiltrating cells. In the presence of B cells, significantly more infiltrating myeloid cells produced IL-10, TGFβ, and IL-35, and fewer produced TNFα, interferon-γ and IL-6 as compared to controls, up to 2 months post-TBI. B cell treatment significantly increased the proportion of CD206+ infiltrating monocytes/macrophages and reduced the relative proportion of activated microglia starting at 4 days and up to 2 months post-injury. Ablation of peripheral monocytes with clodronate liposomes showed that infiltrating peripheral monocytes/macrophages are required for inducing the regulatory phenotype in exogenous B cells. Reciprocally, B cells specifically reduced the expression of inflammatory cytokines in infiltrating Ly6C+ monocytes/macrophages. These data support the hypothesis that peripheral myeloid cells, particularly infiltrating monocyte/macrophages, are key mediators of the neuroprotective immunomodulatory effects observed after B cell treatment.

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Dwyer, L. J., Maheshwari, S., Levy, E., Poznansky, M. C., Whalen, M. J., & Sîrbulescu, R. F. (2023). B cell treatment promotes a neuroprotective microenvironment after traumatic brain injury through reciprocal immunomodulation with infiltrating peripheral myeloid cells. Journal of Neuroinflammation, 20(1). https://doi.org/10.1186/s12974-023-02812-y

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