Regulation and Function of the Caspase-1 in an Inflammatory Microenvironment

Abstract

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.

When Beauty Is Skin Deep: Regulation of the Wound Response by Caspase-8, RIPK3, and the Inflammasome

“…More recently, RIPK3 activity in innateimmune cells has also been shown to regulate the transcription and production of inflammatory cytokines, such as TNF, or activate the NLRP3 inflammasome in a cell-intrinsic manner ( Jamora and colleagues (Lee et al, 2009) documented previously that skin wounding results in reduced caspase-8 expression in the thickened epidermis proximal to a site of wounding and that its expression is restored following wound closure. Similar to these findings, in this issue (Lee et al, 2015), work from the Jamora laboratory demonstrates that an in vitro scratch "wound" ablates caspase-8 protein expression in keratinocytes at the scratch edge and that this correlates directly with increased NF-κB activation and caspase-1 levels. Consistent with these observations being physiologically important, reduced caspase-8 or its mutation is associated with atopic dermatitis (Chun et al, 2002;Li et al, 2010), and keratinocyte-specific deletion of murine caspase-8, or its essential adaptor protein FADD, triggers chronic inflammatory skin disease and the upregulation of many genes induced during epidermal wound healing (Kovalenko et al, 2009;Lee et al, 2009;Li et al, 2010;Bonnet et al, 2011).…”

“…Is the observed NF-κB, caspase-1, and IL-1 axis reported by Jamora and colleagues (Lee et al, 2015) physiologically relevant? Previous research has reported that the chronic skin inflammation resulting from keratinocyte FADD or caspase-8 deletion is not altered by co-deletion of the IL-1R (Kovalenko et al, 2009;Bonnet et al, 2011).…”

“…Caspase-1-induced secretion of IL-1α propagates NF-κB activation and inflammatory gene expression in vivo Lee et al (2015), next asked whether their in vitro findings could also be observed in vivo.…”

“…These findings are in line with those of Kovalenko et al (2009), who concluded that inflammatory signals derive from the suprabasal layer of caspase-8-deficient epidermis. Hence, Jamora and colleagues (Lee et al, 2015) elegantly demonstrate, both in vitro and in vivo, that caspase-1-driven IL-1α secretion in the outer epidermis is likely to amplify NF-κB activation throughout the skin, in either caspase-8 knockout epidermis or as part of the cutaneous wound response.…”

“…Using epidermal explants from mice lacking caspase-8 in keratinocytes (Casp8 fl/fl K14Cre ), Jamora and colleagues (Lee et al, 2015) show that increased caspase-1 expression in these mice is driven specifically by NF-κB binding directly to the caspase-1 promoter. In addition, elevated caspase-1 was observed in epidermis lacking the critical canonical NF-κB inhibitor, IκBα.…”