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

Area of Science:

• Immunology
• Dermatology
• Genetics

Background:

• SHARPIN is a key component of the linear ubiquitin chain assembly complex (LUBAC).
• SHARPIN loss-of-function causes inflammation and lymphoid tissue abnormalities in mice, mimicking human atopic dermatitis (AD).

Purpose of the Study:

• To investigate the role of SHARPIN in the pathogenesis of atopic dermatitis (AD).
• To explore SHARPIN as a potential therapeutic target for AD.

Main Methods:

• Genetic association study of SHARPIN genotypes and haplotypes in AD patients and controls.
• Analysis of SHARPIN expression levels in AD lesions.
• In vitro assays using lentivirus-mediated knockdown of SHARPIN in HaCaT keratinocytes.
• Stimulation assays with cytokines IL-4 and IL-13.

Main Results:

• Identified three mutations in SHARPIN (g.480G>A, g.4576A>G, g.5070C>T) in AD patients.
• Observed significantly decreased SHARPIN expression in AD lesions compared to controls.
• SHARPIN knockdown in keratinocytes elevated IL-33, ST2, FLG, and STAT3 expression, and inactivated NF-κB.
• ST2 expression was further induced by IL-4 and IL-13 in SHARPIN-silenced cells.

Conclusions:

• SHARPIN plays a significant role in AD pathogenesis.
• SHARPIN may represent a novel therapeutic target for atopic dermatitis.