Investigating the Role of Mitophagy in cGAS-STING Inflammation in Chronic Wound Pathogenesis

Résumé

The cGAS-STING pathway stimulates innate immunity, in particular the interferon pathway, which plays an important role in the normal wound healing process. However, chronic wounds can commonly be triggered by prolonged inflammation, impeding progression through the conserved wound healing phases. In recent years, mitochondrial DNA (mtDNA) that has been released into the cytosol has been shown to be a potent stimulator of the cGAS-STING pathway, although this has not been examined in skin. In addition, studies have also demonstrated that dysfunctional mitophagy and therefore the regulation and clearance of damaged mitochondria can lead to elevated immunological responses as well as increased release of mtDNA into the cytoplasm. This has led to the investigation in this project where we explored whether defective mitophagy promotes an increased efflux of mtDNA into the cytosol in skin cell types, thereby stimulating increased cGAS-STING inflammation as a pathogenic mechanism for dysregulated wound healing and chronic wound pathogenesis. Here, in this study, we demonstrate elevated genetic expression of key cGAS-STING pathway components and mitophagy receptors in normal wounded skin as well as chronic wounds compared to intact skin. In addition, we show through in vitro work on skin-related cells that there is an increase in mtDNA in the cytosol of fibroblasts when mitophagy receptors are knocked-down, suggesting that defective mitophagy may be a potential mechanism for prolonged cGAS-STING inflammation in wound healing and the formation of chronic wounds, and warrants further studies.

la date de réponse	22 sept. 2023
langue originale	Anglais
L'institution diplômante	Universite de Namur
Superviseur	Jakob Wikström (Promoteur) & Matthew Hunt (Copromoteur)