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Gene expression changes related to immunosuppression in patients with traumatic brain injury (Part 1)

ABSTRACT: Background : Traumatic brain injury (TBI) can alter various immune functions, including immunosuppression and constitutes a risk factor for nosocomial infections and organ dysfunction. Although TBI can induce a decline in immune cell function, the detailed mechanisms remain unclarified. This study aimed to clarify the mechanism of immunosuppression caused by TBI using a comprehensive transcriptome analysis of immune cells. Methods : Six patients with traumatic brain injury and acute subdural hematoma were admitted to our hospital. We focused on three major subsets of immune cells responsible for the immune response: CD4+ T cells, CD8+ T cells, and monocytes. We evaluated the changes in immune function after injury using comprehensive transcriptome analysis. Blood samples were collected immediately after admission and one week later, and the data were compared with those of healthy volunteers. Results : CD4+ T cells and CD8+ T cells decreased over seven days following injury, and a decrease in cell adhesion and endoplasmic reticulum function was observed. It was suggested that the process of protein synthesis from RNA was impaired and that overall cell function was reduced. Monocytes also show a decrease in endoplasmic reticulum function, but classical and nonclassical monocyte subsets show an increase in functions related to platelet activation and tissue repair. Conclusions : Comprehensive transcriptome analysis confirmed a decrease in endoplasmic reticulum function in CD4+ T cells, CD8+ T cells, and monocytes. This study facilitates further elucidation of the mechanisms of immunosuppression due to trauma and the development of new therapeutic strategies to suppress secondary infections.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285385 | GEO | 2025/08/22

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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Gene expression changes related to immunosuppression in patients with traumatic brain injury (Part 1)

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