Temporal regulation of macrophage polarization by abnormally innervated CGRP + Sensory nerves following spinal cord injury

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.