CGRP sensory neurons promote tissue healing via neutrophils and macrophages

被引：114

作者：

Lu, Yen-Zhen ^{[1
]}

Nayer, Bhavana ^{[1
]}

Singh, Shailendra Kumar ^{[2
]}

Alshoubaki, Yasmin K. ^{[1
]}

Yuan, Elle ^{[1
]}

Park, Anthony J. ^{[1
]}

Maruyama, Kenta ^{[2
,3
]}

Akira, Shizuo ^{[2
]}

Martino, Mikael M. ^{[1
,2
,4
]}

机构：

[1] Monash Univ, Australian Regenerat Med Inst, European Mol Biol Lab Australia, Melbourne, Vic, Australia

[2] Osaka Univ, World Premier Int Res Ctr, Immunol Frontier Res Ctr, Lab Host Def, Osaka, Japan

[3] Aichi Med Univ, Sch Med, Dept Pharmacol, Nagakute, Aichi, Japan

[4] Monash Univ, Victorian Heart Inst, Melbourne, Vic, Australia

来源：

NATURE | 2024年 / 628卷 / 8008期

基金：

英国医学研究理事会;

关键词：

Optics and photonics; Quantum physics; GENE-RELATED PEPTIDE; MUSCLE REGENERATION; THROMBOSPONDIN-1; REPAIR; SKIN; NEUROPEPTIDES; NOCICEPTORS; RESPONSES; BINDING; ROLES;

D O I：

10.1038/s41586-024-07237-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The immune system has a critical role in orchestrating tissue healing. As a result, regenerative strategies that control immune components have proved effective 1,2 . This is particularly relevant when immune dysregulation that results from conditions such as diabetes or advanced age impairs tissue healing following injury 2,3 . Nociceptive sensory neurons have a crucial role as immunoregulators and exert both protective and harmful effects depending on the context 4-12 . However, how neuro-immune interactions affect tissue repair and regeneration following acute injury is unclear. Here we show that ablation of the NaV1.8 nociceptor impairs skin wound repair and muscle regeneration after acute tissue injury. 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, monocytes and macrophages to inhibit recruitment, accelerate death, enhance efferocytosis and polarize macrophages towards a pro-repair phenotype. The effects of CGRP on neutrophils and macrophages are mediated via thrombospondin-1 release and its subsequent autocrine and/or paracrine effects. In mice without nociceptors and diabetic mice with peripheral neuropathies, delivery of an engineered version of CGRP accelerated wound healing and promoted muscle regeneration. Harnessing neuro-immune interactions has potential to treat non-healing tissues in which dysregulated neuro-immune interactions impair tissue healing. Experiments in mouse models show that NaV1.8+ nociceptors innervate sites of injury and provide wound repair signals to immune cells by releasing calcitonin gene-related peptide (CGRP).

引用

页码：604 / 611

页数：8

共 69 条

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