TMEM232 Promotes the Inflammatory Response in Atopic Dermatitis via NF-κB and STAT3 Signaling Pathways.

BACKGROUND: Our group previously found that the transmembrane protein 232 (TMEM232) gene was associated with atopic dermatitis (AD) by Genome-wide association study and fine mapping study. However, its function is unclear so far.

OBJECTIVE: To investigate the roles and mechanisms of TMEM232 in AD.

METHODS: The expression of TMEM232 was investigated in skin lesions of AD patients, MC903-induced AD mouse model, human primary keratinocytes and HaCaT cells stimulated with different inflammatory factors. The role of TMEM232 in AD was analyzed in HaCaT cells and Tmem232 knockout (Tmem232-/-) mice. Tmem232-specific small interfering RNA (siRNA) was used to evaluate its therapeutic potential in the AD mouse model.

RESULTS: The expression of TMEM232 was significantly increased in skin lesions of AD patients，MC903-induced AD mouse model and human primary keratinocytes and HaCaT cells stimulated with different inflammatory factors compared to controls. In the presence of MC903, Tmem232-/- mice exhibited significantly reduced dermatitis severity, mast cell infiltration in the back, and expression of Th1 and Th2-related inflammatory factors in skin tissue compared with WT mice. In vitro and in vivo experiments further showed that the upregulation of TMEM232 in AD exacerbated inflammation response through activating the pathway of nuclear factor-κB and signal transducer and activator of transcription (STAT) 3, and was regulated by IL4/STAT6 axis, which formed a self-amplifying loop. Finally, topical application of Tmem232-siRNA markedly ameliorated AD-like lesions in the AD model.

CONCLUSION: The study first outlines the function of TMEM232. It is involved in regulating inflammation in AD and may be a potential target for AD treatment.