CGRP sensory neurons promote tissue healing by modulating neutrophils and macrophages

Since the immune system plays a critical role in orchestrating tissue healing, regenerative strategies that control immune components have proven effective. This is particularly relevant when immune dysregulation resulting from conditions such as diabetes or advanced age impairs tissue healing following injury. Nociceptive sensory neurons play a crucial role as immunoregulators, exerting both protective and harmful effects depending on the context. However, how neuro-immune interactions impact tissue repair and regeneration after acute injury is unclear. Here, we show that Nav1.8+ nociceptor ablation impairs skin wound repair and muscle regeneration after acute tissue injuries. Nociceptor endings grow into injured skin and muscle tissues and signal to immune cells through the neuropeptide calcitonin gene-related peptide (CGRP) during the healing process. CGRP acts via receptor activity modifying protein 1 (RAMP1) on neutrophils and macrophages to inhibit recruitment, accelerate death, enhance efferocytosis, and polarise macrophages towards a pro-repair phenotype. CGRP effects on neutrophils and macrophages are mediated via thrombospondin-1 release and its subsequent autocrine/paracrine effects. In mice without nociceptors and diabetic mice with peripheral neuropathies, delivering an engineered version of CGRP accelerated wound healing and promoted muscle regeneration. Harnessing neuro-immune interactions holds potential to treat non-healing tissues where dysregulated neuro-immune interactions impair tissue healing. Overall design: To understand the molecular mechanisms by which CGRP modulates neutrophils and macrophages, we performed RNA-seq analysis on bone marrow-derived neutrophils and macrophages stimulated/treated with CGRP (1 nM) or saline control for 4 hours in vitro.