Circulating Ly6Chigh monocyte-derived S100A4+ macrophages exacerbate neuroinflammation and impede recovery of traumatic brain injury

Abstract

Traumatic brain injury (TBI) is now recognized as a systemic disease, yet the molecular and cellular mechanisms involved in the systemic immune response to TBI remain unclear. To address these limitations, we collected the brains and peripheral blood mononuclear cells (PBMCs) from the acute phase of TBI mice and performed single-cell RNA sequencing (scRNA-seq). Here, we identify a population of S100A4⁺ macrophages originating from circulating Ly6C^high monocytes that infiltrate brain tissue following TBI via the CCL4-CCR1 axis, thereby exacerbating brain injury. Further mechanistic studies suggest that enhanced SPP1 output from S100A4⁺ macrophages following TBI triggers a microglial response via the CD44 receptor and exacerbates neuroinflammation. IRF7, as a key transcription factor (TF), drives the activation of S100A4⁺ macrophages following TBI, leading to the corresponding neuroinflammation and neurological deficits. An FDA-approved clinical drug, ursodeoxycholic acid, acts as an IRF7 antagonist to block the activation of S100A4⁺ macrophages, thereby suppressing neuroinflammation and accelerating the recovery of neurological function in TBI mice.