Down-regulated SHARPIN may accelerate the development of atopic dermatitis through activating interleukin-33/ST2 signalling.

SHARPIN is an important component of the linear ubiquitin chain assembly complex (LUBAC). Loss of function of SHARPIN results in eosinophilic inflammation in multiple organs including skin with Th -dominant cytokines and dysregulated development of lymphoid tissues in mice. The clinicopathological features are similar to atopic dermatitis (AD) in humans. In order to investigate the potential role of SHARPIN in the pathogenesis of AD, we performed genetic association study of the genotypes and haplotypes as well as SHARPIN's expression between AD cases and controls. We found three mutations (g.480G>A, g.4576A>G and g.5070C>T) in patient group, and significantly decreased expression in AD lesions, suggesting a primary role of SHARPIN during AD development. Lentivirus-mediated in vitro assays identified that knockdown of SHARPIN can induce elevated expression of IL-33 and its orphan receptor ST2, FLG and STAT3 and NF-κB inactivation in HaCaT keratinocytes, which has been widely evidenced in regulating AD development. ST2 expression was highly induced in SHARPIN-silenced HaCaT keratinocytes after the combined stimulation of IL-4 and IL-13. Our in vivo and in vitro findings implicated that SHARPIN may be a novel participant in the pathogenesis and/or new therapeutic target of AD.