Innate immune activation beyond pathogens: Crosstalk between cellular repair pathways and DAMPs in homeostatic...

Innate immunity has long been viewed as a defense system that evolved to detect and eliminate invading microbes. However, its functions extend beyond pathogen control to the continuous surveillance of cellular integrity. Cellular homeostasis relies on repair mechanisms that preserve genome stability, proteostasis, lipid balance, and organelle quality. When these systems fail, endogenous molecules such as nucleic acids, lipids, protein aggregates, and metabolites become mislocalized or modified and act as damage-associated molecular patterns (DAMPs). These signals mark sites of failed repair and activate innate sensors, sustaining inflammation even in the absence of infection. In this minireview, we outline the major classes of DAMPs and show how their accumulation reflects defects in specific repair pathways. We propose that innate immunity and cellular repair are fundamentally interconnected. When repair is intact, inflammation is transient and resolves. When repair fails, inflammation becomes chronic and drives disease.