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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.

Project description:Introduction: Brain plasticity, synaptic regeneration and neuroinflammation are crucial mechanisms that play important roles in the recovery from acute brain injuries, such as aneurysmal subarachnoid hemorrhage (aSAH), ischemic stroke (IS), and traumatic brain injury (TBI). The p75 neurotrophic receptor (p75NTR) is a significant receptor that modulates brain plasticity, neuroinflammation and apoptosis, making it an interesting target for therapeutic interventions. However, despite the progress made in understanding the molecular mechanisms involved in brain plasticity and neuroinflammation, there are still significant knowledge gaps in identifying protein biomarkers and microRNAs (miRNAs) associated with different types of acute brain injuries. Addressing these gaps will be critical in advancing our understanding of the underlying mechanisms involved in brain injury and developing effective therapies or prognostic strategies for recovery. Hypotheses: We hypothesized that changes in serum levels of p75NTR and its linked neuroinflammatory signaling proteins could predict recovery from acute brain injuries, regardless of injury type. Differentially expressed (DE) circulating miRNAs following acute brain injuries may regulate studied protein targets and overall injury outcome. Methods: A prospective cohort of 74 patients with ischemic stroke (n=30), aneurysmal subarachnoid hemorrhage (n=31), and traumatic brain injury (n=13) was evaluated. Serum samples were collected at two time points after the injury (early at 1.9 ± 1.0 days and late at 5.9 ± 2.2 days) and outcome evaluation was performed after three months. Six proteins were measured using ELISAs: p75NTR, NGF, sortilin, IL1, TNF, and cyclophilin A. A 2-tailed 2-sample t-test, univariate, and multivariate linear discriminant analysis (LDA) was used to compare serum molecules between patients with favorable (modified Rankin Scale (mRS) 0-3) and unfavorable outcome (mRS 4-6). Additionally, circulating miRNAs were extracted from the samples (n=48, early and late) and DE miRNAs were identified using DESeq2. The miRNA putative target genes were predicted and LDA was performed using the normalized expression values of identified DE miRNAs. Results: In this study, p75NTR (p < 0.01) and IL1 (p < 0.05) were found to be independently associated with outcome among the six circulating protein biomarkers studied. Combinatory LDA analysis of all six biomarkers showed significant predictive value for favorable outcome (OR 2.95 (1.46-5.98); area under the curve (AUC)= 71.2%, 95% CI = (0.590-0.833), p = 0.003). Temporal alterations of miRNA expression were observed in the aSAH, TBI, and IS groups (p<0.05, FDR corrected). Twenty-three common miRNAs were identified that differentiated favorable and unfavorable outcome (p<0.05) in all three groups. LDA of four identified miRNAs with predicted targets to studied proteins showed high predictive accuracy (OR (95% CI) 11.7 (2.39-226)); AUC = 94.1%, 95% CI = (0.849 - 1.00), p = 0.016). Conclusions This study indicates that assessing serum levels of p75NTR and its mechanistically linked proteins can predict recovery outcome in patients with different types of acute brain injuries. The combined miRNA and protein biomarker models demonstrated accurate outcome prediction across diverse injury types, implying the presence of a common recovery mechanism. DE miRNAs were found to target the studied molecules, suggesting a potential mechanistical role in recovery. The identified common miRNAs may provide new targets for mechanistic validation in disease models. Further investigation is warranted to validate and explore the potential of these proteins and miRNAs in prognostication and as therapeutic targets for enhancing recovery from acute brain injuries.

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Antimicrobial immunity impedes CNS vascular repair following brain injury

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