Neuroinflammation and immune microenvironment alterations following heat stroke: A transcriptomic perspective

Heat stroke (HS) is a life-threatening condition that provokes severe sterile neuroinflammation in the brain. We performed transcriptomic profiling of brain tissue in a murine HS model to characterize changes in the immune microenvironment. HS induced broad alterations in gene expression, notably upregulating pathways involved in innate immune and inflammatory responses. Gene set enrichment and cell deconvolution analyses revealed an increased representation of peripheral myeloid cells in HS-affected brains, including granulocytes and monocytes/macrophages, alongside markers of activated microglia. Concurrently, many neuronal genes were downregulated, consistent with heat-induced neurodegeneration. Immunohistochemical studies corroborated the transcriptomic data, showing substantial immune cell infiltration and microglial activation in HS brains. In particular, we observed accumulation of eosinophils and elevated expression of both pro-inflammatory (CD80, CD86) and anti-inflammatory (CD206, CD163) macrophage/microglial markers, indicating a complex innate immune response. Exploratory comparisons with published Alzheimer's disease datasets revealed potential parallels in neuroinflammatory signatures, generating the hypothesis that acute HS may engage pathways relevant to chronic neurodegenerative conditions. These findings establish HS as an informative model for studying acute sterile neuroinflammation and its impact on the brain's immune milieu, providing insights that could inform our understanding of neuroimmune mechanisms in both acute injury and neurodegenerative disease.