Calcitonin gene-related peptide inhibits macrophage migration and differentiation via the GTPase Rap1

Root resorption represents a critical complication associated with tooth replantation, directly influencing its success rate. Macrophages, as precursors of odontoclasts, are the primary effector cells that initiate root resorption; however, their cellular and molecular mechanisms of action in that microenvironment are not well understood. In this study, we found that macrophages are juxtaposed with sensory neurons and express receptor activity modifying protein-1（RAMP1,） a receptor for the neuropeptide calcitonin gene-related peptide (CGRP). We hypothesised that CGRP released from sensory neurons in the periodontal microenvironment regulates root resorption by modulating macrophage migration and odontoclast differentiation. To test this hypothesis, we examined the role of CGRP in the regulation of root resorption using a rat tooth replantation model. CGRP, used as a root surface treatment agent, reduced both root and alveolar bone resorption. In vitro, CGRP inhibited the migration of macrophages via the regulation of Rap1/PI3K/Protein kinase B (AKT) signaling axis, indicating a possible cellular cross-talk between sensory neurons and macrophages. Collectively, our findings demonstrate that CGRP-mediated regulation of macrophage migration and odontoclast differentiation through the Rap1/PI3K/AKT signaling axis correlates with reduced root resorption following tooth replantation, suggesting its potential as a candidate therapeutic target for this complication.