The IL-1–Dependent Sterile Inflammatory Response Has a Substantial Caspase-1–Independent Component That Requires Cathepsin C

The sterile inflammatory response to cell death and irritant crystals is medically important because it causes disease. Although these stimuli are structurally distinct, they cause inflammation through a common pathway that requires the cytokine IL-1. In vitro, the inflammasome, and in particular its generation of active caspase-1, is absolutely required to produce bioactive IL-1β. However, in this study, we report that caspase-1 is not required in vivo for much of the IL-1β-dependent sterile inflammatory response. Furthermore, we find that cathepsin C, which controls the activity of a number of leukocyte serine proteases capable of processing IL-1β, plays a major role in this caspase-1-independent pathway. Mice that are deficient in cathepsin C have reduced inflammatory responses to dying cells and silica crystals. In the absence of cathepsin C, caspase-1 becomes rate limiting such that mice doubly deficient in both of these proteases make little IL-1β in vivo and have markedly attenuated inflammatory responses to the sterile stimuli. In contrast, these mutant mice generate normal inflammation in response to exogenous IL-1β, indicating that cathepsin C and caspase-1 function upstream of IL-1β, and, in their absence, all components of the pathway downstream of mature IL-1β are intact.