Abstract
Abstract Genetically inherited autoinflammatory skin disorders are characterized by spontaneous skin inflammation. Mutations in the members of linear ubiquitin chain assembly complex (LUBAC) are associated with spontaneous skin inflammation. Mice, deficient in SHARPIN (Sharpincpdm mice), a member of LUBAC, develop severe dermatitis associated with systemic autoinflammation. Previous studies have demonstrated that NLRP3 inflammasome provoke skin inflammation in Sharpin-deficient mice. However, whether IL-1α or IL-1β instigates disease and, if skin inflammation precedes systemic autoinflammation is not known. Here, we have performed thorough cellular analysis of pre-diseased and diseased Sharpin-deficient mice and demonstrated that systemic inflammation precedes skin inflammation. Furthermore, we demonstrate a specific role for IL-1β, but not IL-1α in instigating disease in Sharpincpdm mice. Our results altogether demonstrate distinct roles of SHARPIN in initiating systemic autoinflammation and skin dermatitis. Furthermore, skin inflammation in Sharpincpdm mice is specifically mediated by IL-1β, highlighting the importance of specific targeted therapies in IL-1 signaling blockade.
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