Sensory neuron TRPV1-mediated macrophage polarization and immune response regulate dental implant osseointegration

Effective and robust osseointegration represents the critical foundation for function and long-term stability of dental implants. Although the immune response has been recognized as a critical orchestrator in this process, the contribution of neuro-immune communication within the peri-implant microenvironment remains largely underexplored. This study aimed to investigate how transient receptor potential vanilloid 1 (TRPV1) in sensory neurons influenced macrophage polarization and immune response during implant osseointegration. In vivo, TRPV1 activation in trigeminal ganglion (TG) enhanced release of calcitonin gene-related peptide (CGRP), which created a regenerative immune milieu through macrophage phenotype modulation and promoted new bone formation around implants. Conversely, TRPV1 inhibition exacerbated inflammation and impaired osseointegration. In vitro, TRPV1-activated sensory neurons induced M2 polarization via CGRP receptor-mediated PI3K/AKT signaling, while suppressing M1 polarization, with corresponding changes in anti- and pro-inflammatory cytokine expression profiles. Collectively, these findings revealed a neuro-immune regulatory mechanism whereby sensory neurons fine-tune macrophage functions to shape the peri-implant microenvironment, ultimately facilitating osseointegration. This work provided crucial insights into the neuro-immune mechanisms governing peri-implant bone healing, suggesting potential therapeutic targets for improving dental implant outcomes.