The study investigates the role of nociceptive sensory neurons in promoting tissue healing through their release of calcitonin gene-related peptide (CGRP) and its interaction with neutrophils and macrophages. Key findings include: 1. **Ablation of Naᵥ1.8 nociceptors impairs tissue healing**: Mice lacking Naᵥ1.8 nociceptors show delayed skin wound closure and impaired muscle regeneration compared to controls. 2. **CGRP signaling modulates immune cells**: CGRP acts via receptor activity-modifying protein 1 (RAMP1) on neutrophils and macrophages to inhibit their recruitment, accelerate their death, enhance efferocytosis, and polarize macrophages towards a pro-repair phenotype. 3. **Thrombospondin-1 (TSP-1) mediates CGRP effects**: CGRP-induced TSP-1 expression in neutrophils and macrophages limits their accumulation, accelerates their death, and promotes macrophage polarization towards an anti-inflammatory and pro-repair phenotype. 4. **eCGRP enhances tissue healing in diabetic mice**: Engineered CGRP with enhanced retention and protection (eCGRP) improves wound closure and muscle regeneration in diabetic mice, which exhibit peripheral neuropathy and impaired tissue healing. 5. **Conclusion**: The study highlights a neuro-immune regenerative axis where CGRP and nociceptors play crucial roles in promoting tissue healing, particularly in conditions like diabetes where immune dysregulation impairs healing. This axis offers potential for therapeutic interventions in non-healing tissues.The study investigates the role of nociceptive sensory neurons in promoting tissue healing through their release of calcitonin gene-related peptide (CGRP) and its interaction with neutrophils and macrophages. Key findings include: 1. **Ablation of Naᵥ1.8 nociceptors impairs tissue healing**: Mice lacking Naᵥ1.8 nociceptors show delayed skin wound closure and impaired muscle regeneration compared to controls. 2. **CGRP signaling modulates immune cells**: CGRP acts via receptor activity-modifying protein 1 (RAMP1) on neutrophils and macrophages to inhibit their recruitment, accelerate their death, enhance efferocytosis, and polarize macrophages towards a pro-repair phenotype. 3. **Thrombospondin-1 (TSP-1) mediates CGRP effects**: CGRP-induced TSP-1 expression in neutrophils and macrophages limits their accumulation, accelerates their death, and promotes macrophage polarization towards an anti-inflammatory and pro-repair phenotype. 4. **eCGRP enhances tissue healing in diabetic mice**: Engineered CGRP with enhanced retention and protection (eCGRP) improves wound closure and muscle regeneration in diabetic mice, which exhibit peripheral neuropathy and impaired tissue healing. 5. **Conclusion**: The study highlights a neuro-immune regenerative axis where CGRP and nociceptors play crucial roles in promoting tissue healing, particularly in conditions like diabetes where immune dysregulation impairs healing. This axis offers potential for therapeutic interventions in non-healing tissues.