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Antimicrobial immunity impedes CNS vascular repair following brain injury

ABSTRACT: Traumatic brain injuries (TBI) and cerebrovascular injuries are leading causes of disability and mortality worldwide. Systemic infections often accompany these disorders, which can impede recovery and significantly worsen outcomes. Remodeling of the central nervous system (CNS) after injury is essential for functional recovery and depends on temporally and spatially coordinated innate immune responses; however, the effect of systemic infections on this process is not well understood. Here, we demonstrate that a broad range of systemically introduced microbes and pathogen-associated molecular patterns interfered with immune-mediated meningeal vascular repair after TBI, with sequential infections promoting a prolonged state of disrepair. Mechanistically, we discovered that MDA5-dependent detection of a noncytopathic arenavirus encountered after TBI disrupted pro-angiogenic programming in recruited myeloid cells via local induction of type I interferon signaling. Systemic viral infection similarly promoted type I interferon-dependent impairment of restorative angiogenesis in the brain parenchyma after intracranial hemorrhage, leading to chronic blood brain barrier leakage, sustained interferon signaling, and a failure to restore cognitive-motor function. Our findings reveal an immunological mechanism by which systemic infections deviate reparative programming after CNS injury and offer a new therapeutic target to improve recovery and prevent states of prolonged neurological decline.

ORGANISM(S): Mus musculus

PROVIDER: GSE172102 | GEO | 2021/07/27

REPOSITORIES: GEO

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Project description:Traumatic brain injury (TBI) induces neuroinflammatory innate immune responses that plays roles in both worsening brain damage and facilitating functional recovery. A major goal is to understand the heterogeneity of the immune responses to TBI, and to precisely identify key components that impact functional outcomes. We previously demonstrated that genetically targeting Ccr2 in a mouse model of controlled cortical impact led to neuroprotection in TBI. Our current studies of TBI use single cell RNA sequencing of over 10,000 TBI ipsilateral brain leukocytes to examine the mechanisms associated with the observed benefit in Ccr2-/- mice by comparing gene expression in leukocyte subsets from Ccr2-/- mice to gene expression in C57BL/6 wild type mice. Unbiased clustering identified two monocyte subsets, Chil3hi Ly6Chi classical monocytes and Gpnmbhi Ly6Clo nonclassical monocytes, and nine microglia states in the ipsilateral TBI brain. Comparative analysis between the genotypes revealed that Ccr2-/- TBI mice contained reduced numbers of inflammatory macrophages. In TBI, we observed a subset of microglia highly expressing several type I interferon-stimulated genes (ISGs) and is designated as Irf7hi microglia. Notably, unbiased differential expression analysis detected a two-fold reduction in the type I interferon response in multiple Ccr2-/- TBI microglia subsets compared to wild type TBI microglia. Treatment post-injury with a human CCR2 (hCCR2) inhibitor, CCX872, in hCcr2 knock-in mice improved cognitive function post-TBI, and also correlated with reduced expression of a key ISG, Irf7. We identified and characterized macrophage and microglia subsets during acute TBI. Our data showed that a reduction in macrophage expansion in TBI by both genetic and pharmacological methods, improved TBI and correlated with a reduction in the type I IFN response. These data indicate that macrophage expansion co-directs a type IFN response in microglia, and that targeting macrophage expansion in the brain can alter the profile of microglia subsets and lead towards improved functional outcomes.

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Antimicrobial immunity impedes CNS vascular repair following brain injury

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