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Single-cell transcriptomics of resected human traumatic brain injury tissues reveals acute activation of endogenous retroviruses in oligodendroglia

ABSTRACT: Traumatic brain injury (TBI) is a leading cause of chronic brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes to the long-term pathology. We used snRNA-seq to study transcriptomic changes in different cell populations in human brain tissue obtained acutely after severe, life-threatening TBI. This revealed a unique transcriptional response in oligodendrocyte precursors and mature oligodendrocytes, including the activation of a robust innate immune response, indicating an important role for oligodendroglia in the initiation of neuroinflammation. The activation of an innate immune response correlated with transcriptional upregulation of endogenous retroviruses in oligodendroglia. This observation was causally linked in vitro using human glial progenitors, implicating these ancient viral sequences in human neuroinflammation. In summary, this work provides a unique insight into the initiating events of the neuroinflammatory response in TBI, which has new therapeutic implications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE209552 | GEO | 2023/03/03

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:Acute cognitive impairment (i.e., delirium) is common in elderly emergency department patients and frequently results from infections that are unrelated to the central nervous system. Since activation of the peripheral innate immune system induces brain microglia to produce inflammatory cytokines that are responsible for behavioral deficits, we investigated if aging exacerbated neuroinflammation and sickness behavior after peripheral injection of lipopolysaccharide (LPS). Microarray analysis revealed a transcriptional profile indicating the presence of primed or activated microglia and increased inflammation in the aged brain. Furthermore, aged mice had a unique gene expression profile in the brain after an intraperitoneal injection of LPS, and the LPS-induced elevation in the brain inflammatory cytokines and oxidative stress was both exaggerated and prolonged compared with adults. Aged mice were anorectic longer and lost more weight than adults after peripheral LPS administration. Moreover, reductions in both locomotor and social behavior remained 24 h later in aged mice, when adults had fully recovered, and the exaggerated neuroinflammatory response in aged mice was not reliably paralleled by increased circulating cytokines in the periphery. Taken together these data establish that activation of the peripheral innate immune system leads to exacerbated neuroinflammation in the aged as compared with adult mice. This dysregulated link between the peripheral and central innate immune system is likely to be involved in the severe behavioral deficits that frequently occur in older adults with systemic infections. Experiment Overall Design: In this study, adult and aged mice were injected intraperitoneal with sterile saline or Escherichia coli LPS (0.33 mg/kg, ~10 µg/mouse; serotype 0127:B8, Sigma). This dosage of LPS was used because it induces a mild transient sickness behavior in young adults. Mice were killed 4 h after saline or LPS injection by CO2 asphyxiation. Blood samples were collected and brains were removed, separated in half at the longitudinal fissure, frozen in liquid nitrogen, and stored (-80°C) until assaying. Total RNA was later isolated from some brain samples for microarray analysis (n=3).

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Single-cell transcriptomics of resected human traumatic brain injury tissues reveals acute activation of endogenous retroviruses in oligodendroglia

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