Regulation and function of the caspase-1 in an inflammatory microenvironment

The inflammasome is a complex of proteins that plays a critical role in mounting an inflammatory response in reply to a harmful stimulus that compromises the homeostatic state of the tissue. The NLRP3 inflammasome, which is found in a wound-like environment, is comprised of three components: the NLRP3, the adaptor protein ASC and caspase-1. Interestingly, while ASC levels do not fluctuate, caspase-1 levels are elevated in both physiological and pathological conditions. Despite the observation that merely raising caspase-1 levels is sufficient to induce inflammation, the crucial question regarding the mechanism governing its expression is unexplored. We find that in an inflammatory microenvironment, caspase-1 is regulated by NFκB. Consistent with this association, the inhibition of caspase-1 activity parallels the effects on wound-healing caused by the abrogation of NFκB activation. Surprisingly, not only does inhibition of the NFκB/caspase-1 axis disrupt the inflammatory phase of the wound-healing program, it also impairs the stimulation of cutaneous epithelial stem cells of the proliferative phase. These data provide a mechanistic basis for the complex interplay between different phases of the wound-healing response in which the downstream signaling activity of immune cells can kindle the amplification of local stem cells to advance tissue repair.