# Neutrophil-initiated nociceptive ingrowth orchestrates inflammation resolution to potentiate bone regeneration

## TL;DR

Nociceptive nerves help resolve inflammation during bone healing by working with neutrophils and osteoblasts, offering new treatment ideas for inflammatory bone diseases.

## Contribution

Discovery of a neuroimmune feedback loop involving neutrophils, nociceptors, and osteoblasts that regulates inflammation resolution during bone regeneration.

## Key findings

- Neutrophils trigger nociceptive ingrowth that suppresses inflammation via LXA4 production in osteoblasts.
- Nociceptor-derived CGRP activates osteoblastic autophagy to promote LXA4 biosynthesis.
- Reduced nociceptive innervation in diabetic patients correlates with impaired bone healing and increased inflammation.

## Abstract

Nociceptive pain is a cardinal feature of traumatic and inflammatory bone diseases. However, whether and how nociceptors actively regulate the immune response during bone regeneration remains unclear. Here, we found that neutrophil-triggered nociceptive ingrowth functioned as negative feedback regulation to inflammation during bone healing. A unique Il4ra+Ccl2high neutrophil subset drove intense postinjury TRPV1+ nociceptive ingrowth, which in return dissipated inflammation by activating the production of pro-resolving mediator lipoxin A4 (LXA4) in osteoblasts. Mechanistically, osteoblastic autophagy activated by nociceptor-derived calcitonin gene-related peptide (CGRP) suppressed the nuclear translocation of arachidonate 5-lipoxygenase (5-LOX) to favor the LXA4 biosynthesis. Moreover, in alveolar bone from patients with Type II diabetes, we found diminished nociceptive innervation correlated with reduced autophagy, increased inflammation, and impaired bone formation. Activating nociceptive nerves by spicy diet or topical administration of a clinical-approved TRPV1 agonist showed therapeutic benefits on alveolar bone healing in diabetic mice. These results reveal a critical neuroimmune interaction underlying the inflammation-regeneration balance during bone repairing and may lead to novel therapeutic strategies for inflammatory bone diseases.