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- Title
Pannexin 1 drives efficient epithelial repair after tissue injury.
- Authors
Lucas, Christopher D.; Medina, Christopher B.; Bruton, Finnius A.; Dorward, David A.; Raymond, Michael H.; Tufan, Turan; Etchegaray, J. Iker; Barron, Brady; Oremek, Magdalena E. M.; Arandjelovic, Sanja; Farber, Emily; Onngut-Gumuscu, Suna; Ke, Eugene; Whyte, Moira K. B.; Rossi, Adriano G.; Ravichandran, Kodi S.
- Abstract
Epithelial tissues such as lung and skin are exposed to the environment and therefore particularly vulnerable to damage during injury or infection. Rapid repair is therefore essential to restore function and organ homeostasis. Dysregulated epithelial tissue repair occurs in several human disease states, yet how individual cell types communicate and interact to coordinate tissue regeneration is incompletely understood. Here, we show that pannexin 1 (Panx1), a cell membrane channel activated by caspases in dying cells, drives efficient epithelial regeneration after tissue injury by regulating injury-induced epithelial proliferation. Lung airway epithelial injury promotes the Panx1-dependent release of factors including ATP, from dying epithelial cells, which regulates macrophage phenotype after injury. This process, in turn, induces a reparative response in tissue macrophages that includes the induction of the soluble mitogen amphiregulin, which promotes injury-induced epithelial proliferation. Analysis of regenerating lung epithelium identified Panx1-dependent induction of Nras and Bcas2, both of which positively promoted epithelial proliferation and tissue regeneration in vivo. We also established that this role of Panx1 in boosting epithelial repair after injury is conserved between mouse lung and zebrafish tailfin. These data identify a Panx1-mediated communication circuit between epithelial cells and macrophages as a key step in promoting epithelial regeneration after injury. Partnering to promote epithelial repair: Repair of epithelial tissues such as the lungs is essential for restoring organ and barrier function after infection or disease. Lucas et al. demonstrate that damaged epithelial cells initiate repair by releasing intracellular factors through pannexin channels that subsequently activate pro-regenerative macrophage responses. In mice experiencing naphthalene-induced lung injury and zebrafish undergoing tailfin transection, genetic inhibition of Panx1 impaired epithelial proliferation and repair, a process that required both alveolar and interstitial macrophage populations. Pannexin 1–released factors including ATP promoted macrophage production of the epithelial cell mitogen amphiregulin, which was required for epithelial repair. These results identify an important role for pannexin 1 channels in establishing communication between damaged epithelium and macrophages that is required for subsequent tissue repair.
- Publication
Science Immunology, 2022, Vol 7, Issue 71, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.abm4032