TY - JOUR
T1 - CGRP sensory neurons promote tissue healing via neutrophils and macrophages
AU - Lu, Yen-Zhen
AU - Nayer, Bhavana
AU - Singh, Shailendra Kumar
AU - Alshoubaki, Yasmin K.
AU - Yuan, Elle
AU - Park, Anthony J.
AU - Maruyama, Kenta
AU - Akira, Shizuo
AU - Martino, Mikaël M.
N1 - Funding Information:
The authors thank S. N. Lau and E. Tang for assistance with histology processing; A. Fernandes for assistance with the initial wound healing experiments; the Monash Histology Platform; T. Wilson for RNA-seq; the Monash Bioinformatics Platform for assistance with RNA-seq analysis; K. Tsujikawa for providing Ramp1 sperm; M. Ikawa, K. Kaseda and N. Furuta for in vitro fertilization of Ramp1 mice; H. Tanaka for assistance with LysM mice transfer form RIKEN BioResource Research Center; and J. M. D. Legrand for detailed reading of the manuscript. Extended Data Fig. 10 was created with BioRender.com. This work was funded in part by the National Health and Medical Research Council (APP1140229 and APP1176213) to M.M.M., the Viertel Charitable Foundation Senior Medical Researcher Fellowship to M.M.M. and the Osaka University International Joint Research Promotion Program to S.A. The Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government.
Publisher Copyright:
© The Author(s) 2024.
PY - 2024/4/18
Y1 - 2024/4/18
N2 - The immune system has a critical role in orchestrating tissue healing. As a result, regenerative strategies that control immune components have proved effective1,2. This is particularly relevant when immune dysregulation that results from conditions such as diabetes or advanced age impairs tissue healing following injury2,3. Nociceptive sensory neurons have a crucial role as immunoregulators and exert both protective and harmful effects depending on the context4–12. 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.
AB - The immune system has a critical role in orchestrating tissue healing. As a result, regenerative strategies that control immune components have proved effective1,2. This is particularly relevant when immune dysregulation that results from conditions such as diabetes or advanced age impairs tissue healing following injury2,3. Nociceptive sensory neurons have a crucial role as immunoregulators and exert both protective and harmful effects depending on the context4–12. 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.
UR - http://www.scopus.com/inward/record.url?scp=85188837259&partnerID=8YFLogxK
U2 - 10.1038/s41586-024-07237-y
DO - 10.1038/s41586-024-07237-y
M3 - Article
C2 - 38538784
AN - SCOPUS:85188837259
SN - 0028-0836
VL - 628
SP - 604
EP - 611
JO - Nature
JF - Nature
IS - 8008
ER -
