TMEM232 promotes the inflammatory response in atopic dermatitis via the nuclear factor-κB and signal transducer and activator of transcription 3 signalling pathways

TMEM232 is regulated by the interleukin-4/signal transducer and activator of transcription 6 (IL-4/STAT6) axis and promotes the inflammatory response in atopic dermatitis (AD). TMEM232 promotes keratinocyte inflammation by activating nuclear factor-kappa B and STAT3 pathways to release alarmins, such as IL-33, thymic stromal lymphopoietin and various cytokines and chemokines to induce a T-helper 2 inflammatory response and is regulated by the IL-4/STAT6 axis, which forms positive feedback that exacerbates AD symptoms. 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. Objectives To investigate the roles and mechanisms of TMEM232 in AD. Methods The expression of TMEM232 was investigated in skin lesions of patients with AD, the MC903-induced AD mouse model, human primary keratinocytes and immortalized human keratinocyte cell line (HaCaT) cells stimulated with different inflammatory factors. The role of TMEM232 in AD was analysed 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 patients with AD, the MC903-induced AD mouse model and human primary keratinocytes and HaCaT cells stimulated with different inflammatory factors compared with controls. In the presence of MC903, Tmem232(-/-) mice exhibited significantly reduced dermatitis severity, mast-cell infiltration in the back, and expression of T-helper (Th)1 and Th2-related inflammatory factors in skin tissue compared with wild-type mice. In vitro and in vivo experiments further showed that upregulation of TMEM232 in AD exacerbated the inflammation response through activating the pathway of nuclear factor-kappa B and signal transducer and activator of transcription (STAT) 3, and was regulated by the interleukin-4/STAT6 axis, which formed a self-amplifying loop. Finally, topical application of Tmem232 siRNA markedly ameliorated AD-like lesions in the AD model. Conclusions This study is the first to outline the function of TMEM232. It is involved in regulating inflammation in AD and may be a potential target for AD treatment.