Meningeal macrophages regulate fibroblasts to influence meningeal lymphatic function following traumatic brain injury.

Abstract

BACKGROUND: The meningeal lymphatic system represents a critical pathway for cerebrospinal fluid exchange, waste clearance, and immune cell trafficking in the central nervous system. Although traumatic brain injury (TBI) induces marked alterations in meningeal immune cells, their role in regulating meningeal lymphatic function under physiological and pathological conditions remains unclear. METHODS: Single-cell RNA sequencing, confocal microscopy, and flow cytometry were performed to identify a distinct population of meningeal fibroblasts that secrete VEGF-C and to investigate alterations in this population following TBI. By subdural injection of clodronate liposomes and PDGF-C, the role of meningeal resident macrophages and their secreted PDGF-C in regulating meningeal lymphatic function was further examined. RESULTS: A distinct population of meningeal fibroblasts was identified as a source of VEGF-C, whose production is regulated by meningeal macrophages through the PDGF-C/PDGFRα axis. In the early phase of TBI, depletion of resident meningeal macrophages impaired fibroblast-derived VEGF-C production. Further investigations revealed that macrophage depletion resulted in severe meningeal lymphatic dysfunction. Conversely, subdural administration of PDGF-C after TBI enhanced fibroblast-derived VEGF-C production, restored meningeal lymphatic function, alleviated neuroinflammation, and promoted myelin integrity. CONCLUSION: Overall, our findings emphasize that meningeal resident macrophages can regulate fibroblast-derived VEGF-C production via PDGF-C, thereby influencing meningeal lymphatic function, and thus propose a novel therapeutic strategy to enhance neurological repair after TBI.