Sensory nerve-derived semaphorin 3A promotes bone healing through macrophage immunomodulation

Sensory innervation has emerged as a crucial regulator of skeletal homeostasis and regeneration. Growing evidence indicates that disruption of sensory nerves is associated with excessive inflammation and impaired tissue healing. However, the underlying mechanisms by which neuronal signaling regulates the immune microenvironment to orchestrate bone repair remain unclear. In this study, we investigated the role of semaphorin 3A (Sema3A), secreted by sensory nerves, in macrophage immunomodulation during bone healing. Knockdown of Sema3A in dorsal root ganglion (DRG) aggravated local inflammation and impaired new bone formation in femoral defects in mice, whereas exogenous Sema3A supplementation attenuated the inflammatory milieu and restored regenerative capacity. In vitro, Sema3A deficiency in DRG neurons exacerbated M1 polarization and pro-inflammatory cytokine production, while exogenous Sema3A treatment facilitated macrophage polarization toward the M2 reparative phenotype. Mechanistically, macrophage phenotypic transition from M1 to M2 induced by Sema3A was associated with suppression of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling pathway. Blocking NLRP3 inflammasome activation could further mitigate macrophage-mediated inflammatory response and subsequently potentiate osteogenic potential. Collectively, these findings identify sensory nerve-derived Sema3A as a key mediator of macrophage immunomodulation that shapes a pro-regenerative microenvironment, thereby promoting bone healing. Our work provides novel insights into the neuro-immune-bone regulatory axis and may lead to promising therapeutic strategies for enhancing bone regeneration.