Spinal cord injury (SCI) initiates a complex neuroimmune cascade, where the interplay between damaged neural circuits and the inflammatory response critically determines clinical outcomes. A pivotal but poorly understood aspect of this interplay is the aberrant regeneration of CGRP⁺ sensory nerve fibers and their dynamic communication with immune cells. This review systematically delineates the spatiotemporal remodeling of CGRP⁺ fibers post-SCI and elucidates their time-dependent regulation of macrophage polarization. We synthesize emerging evidence on how CGRP signaling, through receptors like CLR/RAMP1 and downstream pathways (e.g., cAMP/PKA, MAPK), fine-tunes the macrophage polarization continuum across different injury phases, thereby influencing the neuroimmune microenvironment. Furthermore, we explore the synergistic actions of CGRP with other neuropeptides and the cross-regulation with key inflammatory signaling hubs, such as NF-κB and STAT3. By integrating these multifaceted interactions, this review not only provides a novel perspective on the neuroimmune pathogenesis of SCI but also highlights the therapeutic potential of targeting the CGRP pathway to foster neural repair and restore immune homeostasis.
Hu et al. (Fri,) studied this question.