IL-1 family cytokines serve as 'activity recognition receptors' for aberrant protease activity indicative of danger.

Members of the extended IL-1 cytokine family play key roles as instigators of inflammation in numerous infectious and sterile injury contexts and are highly enriched at barrier surfaces such as the skin, lungs and intestinal mucosa. Because IL-1 family cytokines do not possess conventional ER-golgi trafficking and secretory signals, these cytokines are typically released into the extracellular space due to tissue damage resulting in necrosis, or pathogen detection resulting in pyroptosis. The latter feature, in combination with other factors, suggests that IL-1 family cytokines serve as canonical damage-associated molecular patterns (DAMPs), which instigate inflammation in response to tissue damage. However, IL-1 family cytokines also require a proteolytic activation step and diverse intracellular, extracellular and non-self proteases have been identified that are capable of processing and activating members of this family. This suggests that IL-1 family members function as sentinels for aberrant protease activity, which is frequently associated with infection or tissue damage. Here, we overview the diversity of proteases implicated in the activation of IL-1 family cytokines and suggest that this ancient cytokine family may have evolved to complement 'pattern recognition receptors', by serving as 'activity recognition receptors' enabling the detection of aberrant enzyme activity indicative of 'danger'.