Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin disease

Abstract

Expression of enzymatically inactive caspase-8, or deletion of caspase-8 from basal epidermal keratinocytes, triggers chronic skin inflammation in mice. Unlike similar inflammation resulting from arrest of nuclear factor B activation in the epidermal cells, the effect induced by caspase-8 deficiency did not depend on TNF, IL-1, dermal macrophage function, or expression of the toll-like receptor adapter proteins MyD88 or TRIF. Both interferon regulatory factor (IRF) 3 and TANK-binding kinase were constitutively phosphorylated in the caspase-8-deficient epidermis, and knockdown of IRF3 in the epidermis-derived cells from these mice abolished the expression of up-regulated genes. Temporal and spatial analyses of the alterations in gene expression that result from caspase-8 deficiency reveal that the changes are initiated before birth, around the time that cornification develops, and occur mainly in the suprabasal layer. Finally, we found that caspase-8-deficient keratinocytes display an enhanced response to gene activation by transfected DNA. Our findings suggest that an enhanced response to endogenous activators of IRF3 in the epidermis, presumably generated in association with keratinocyte differentiation, contributes to the skin inflammatory process triggered by caspase-8 deficiency.

Old, new and emerging functions of caspases

“…Previous studies have also reported an inflammasome-independent role for caspase-8 in inhibiting extensive inflammation in vivo. 72,73 Conditional deletion of caspase-8 in hepatocytes, augments Listeria infection in liver and chronic inflammation following hepatectomy. 73 Caspase-8 deficiency also protects against inflammation-related hepatocarcinogenesis, while inducing Although Ub-RIP1 can enhance the phosphorylation of IRF3, it is also cleaved by activated caspase-8.…”

“…74 In addition, conditional deletion of caspase-8 in epidermal keratinocytes, is associated with chronic skin inflammatory disease associated with constitutive IRF3 signaling. 72 Interestingly, this role for caspase-8 in suppressing inflammation is independent of signaling mediated through TNF, IL-1β or TLR receptors and independent of NFκβ signaling. Instead, caspase-8 regulates the activation of the IκK-related, TANK-binding kinase 1 (TBK1) and IRF3 to downregulate the inflammatory response.…”

“…Instead, caspase-8 regulates the activation of the IκK-related, TANK-binding kinase 1 (TBK1) and IRF3 to downregulate the inflammatory response. 72 Later reports demonstrated that caspase-8 suppresses inflammation following viral RNA-induced RIG-1 signaling 75 by interaction with the RIG-I signaling complex, RIP1 cleavage and inhibition of IRF3-mediated activation of interferons ( Figure 3). 75 Mutations in NALP3 and defective inflammasomes are associated with innate-immune-mediated diseases, and aberrant IL-1 processing has been reported in numerous autoinflammatory diseases including gout, diabetes and juvenileonset arthritis.…”

TAK1 control of cell death

“…For example, either Tak1 or caspase-8 deletion in the epidermis results in psoriasis-like skin inflammation resulting in animal mortality around postnatal days 5-8 (P5-8). 82,92 Inducible deletion of Tak1 or caspase-8 in the intestinal epithelium causes IBD-like intestinal inflammation, which is associated with loss of a specific cell type known as paneth cells. 55,93 Similarly, epidermal-and intestinal epithelium-specific deletion of Fadd, which abrogates caspase-8 activation, causes inflammatory skin disease and IBD-like ileitis.…”

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

“…Caspase-8-deficient epidermal cells show an increased inflammatory response towards transfected DNA, leading to chronic skin inflammation (Kovalenko et al 2009). …”