Yanya Lin, Chengda Lin, Jianhui Chen, Shijun Chen, Jianhuang Huang, Jianxiong Hu
These findings provide transcriptomic and in vitro evidence supporting a PVM-derived MIF-ACKR3-STAT3 signaling axis associated with endothelial activation-related molecular changes in acute TBI. Direct functional effects on BBB integrity and in vivo relevance require further validation. This candidate axis highlights perivascular immune-vascular crosstalk as a potential avenue for therapeutic investigation.
BACKGROUND: Blood-brain barrier (BBB) disruption is a hallmark of acute traumatic brain injury (TBI), yet the immune-vascular mechanisms underlying endothelial dysfunction remain incompletely understood. Perivascular macrophages (PVMs) are strategically positioned to modulate cerebrovascular homeostasis, but their role in acute post-traumatic endothelial activation has not been systematically characterized.
METHODS: We re-analyzed a publicly available mouse single-cell RNA sequencing (scRNA-seq) dataset (GSE290150, 24 h post-TBI) to characterize the landscape of immune and vascular cell populations and to infer intercellular communication. Bone marrow-derived macrophages (BMDMs) served as a PVM surrogate model, and bEnd.3 cerebral endothelial cells were used for in vitro validation of key signaling pathways.
RESULTS: Single-cell analysis revealed concurrent expansion of PVM-like cells and activated endothelial cells (Activated ECs) in the TBI brain, with CellChat-predicted enhancement of MIF-ACKR3 signaling from PVM-like cells toward Activated ECs. Inflammatory stimulation of BMDMs significantly increased MIF expression and secretion in a STAT3-dependent manner. Macrophage-conditioned medium induced endothelial activation-associated molecular changes, including upregulation of Angpt2 and Adm and downregulation of tight junction genes Claudin5 and Tjp1; these effects were attenuated by MIF inhibitor ISO-1 or ACKR3 antagonist CCX771. Recombinant MIF dose-dependently reproduced these changes, which were substantially abrogated by ACKR3 pharmacological blockade or siRNA knockdown. STAT3 inhibition further suppressed rMIF-induced endothelial transcriptional responses.
CONCLUSION: These findings provide transcriptomic and in vitro evidence supporting a PVM-derived MIF-ACKR3-STAT3 signaling axis associated with endothelial activation-related molecular changes in acute TBI. Direct functional effects on BBB integrity and in vivo relevance require further validation. This candidate axis highlights perivascular immune-vascular crosstalk as a potential avenue for therapeutic investigation.