RRC ID 59140
Author Weavers H, Wood W, Martin P.
Title Injury Activates a Dynamic Cytoprotective Network to Confer Stress Resilience and Drive Repair.
Journal Curr Biol
Abstract In healthy individuals, injured tissues rapidly repair themselves following damage. Within a healing skin wound, recruited inflammatory cells release a multitude of bacteriocidal factors, including reactive oxygen species (ROS), to eliminate invading pathogens. Paradoxically, while these highly reactive ROS confer resistance to infection, they are also toxic to host tissues and may ultimately delay repair. Repairing tissues have therefore evolved powerful cytoprotective "resilience" machinery to protect against and tolerate this collateral damage. Here, we use in vivo time-lapse imaging and genetic manipulation in Drosophila to dissect the molecular and cellular mechanisms that drive tissue resilience to wound-induced stress. We identify a dynamic, cross-regulatory network of stress-activated cytoprotective pathways, linking calcium, JNK, Nrf2, and Gadd45, that act to both "shield" tissues from oxidative damage and promote efficient damage repair. Ectopic activation of these pathways confers stress protection to naive tissue, while their inhibition leads to marked delays in wound closure. Strikingly, the induction of cytoprotection is tightly linked to the pathways that initiate the inflammatory response, suggesting evolution of a fail-safe mechanism for tissue protection each time inflammation is triggered. A better understanding of these resilience mechanisms-their identities and precise spatiotemporal regulation-is of major clinical importance for development of therapeutic interventions for all pathologies linked to oxidative stress, including debilitating chronic non-healing wounds.
Volume 29(22)
Pages 3851-3862.e4
Published 2019-11-18
DOI 10.1016/j.cub.2019.09.035
PII S0960-9822(19)31197-2
PMID 31668626
PMC PMC6868510
MeSH Animals Calcium / metabolism Cytoprotection / genetics Cytoprotection / physiology* Drosophila Proteins / metabolism Drosophila melanogaster / metabolism Inflammation / pathology Intracellular Signaling Peptides and Proteins MAP Kinase Signaling System NF-E2-Related Factor 2 Oxidation-Reduction Oxidative Stress / genetics Oxidative Stress / physiology* Reactive Oxygen Species / metabolism Wound Healing / genetics Wound Healing / physiology*
IF 9.601
Times Cited 2
Drosophila DGRC#109007