Autoinflammatory Skin Disorders: The Inflammasomme in Focus

Autoinflammatory skin disorders are a group of heterogeneous diseases that include diseases such as cryopyrin-associated periodic syndrome (CAPS) and familial Mediterranean fever (FMF). Therapeutic strategies targeting IL-1 cytokines have proved helpful in ameliorating some of these diseases. While inflammasomes are the major regulators of IL-1 cytokines, inflammasome-independent complexes can also process IL-1 cytokines. Herein, we focus on recent advances in our understanding of how IL-1 cytokines, stemming from inflammasome-dependent and -independent pathways are involved in the regulation of skin conditions. Importantly, we discuss several mouse models of skin inflammation generated to help elucidate the basic cellular and molecular effects and modulation of IL-1 in the skin. Such models offer perspectives on how these signaling pathways could be targeted to improve therapeutic approaches in the treatment of these rare and debilitating inflammatory skin disorders.

TrendsThe skin harbors specific commensal microbiota with many known roles in modulating tissue homeostasis and controlling immunity. Limiting gut microbiota in murine models of cryopyrin-associated periodic syndrome (CAPS) delays the onset of disease.More than 175 different sequence variants of the NLRP3 inflammasome have been linked to skin inflammation in CAPS patients. IL-1β-specific blocking antibodies are effective in suppressing CAPS symptoms. Mice carrying similar NLRP3 gain-of-function (GOF) mutations have significantly enhanced our current understanding of CAPS.GOF mutations in the B30.2 domain of PYRIN in humans result in skin Familial-Mediterranean fever (FMF). Transgenic mice expressing chimeric PYRIN (murine PYRIN fused with the human B30.2 domain containing FMF mutations) have facilitated our understanding of FMF.SHARPIN deficiency (a member of LUBAC) promotes inflammatory skin disease. Aberrant TNF-TNFR signaling as well as NLRP3 inflammasome activation contributes to disease development in SHARPIN-deficient mice.SHARPIN appears to have cell-type specific roles in regulating inflammasome activation and cell death.Ptpn6spin mice are used as a model of neutrophilic dermatoses and have revealed a specific role for IL-1α, but not IL-1β, in instigating this inflammatory skin disease. The involvement of RIPK1 suggests that cell death pathways might be critical in this disease.