Role of N6-methyladenosine RNA modification in the imbalanced inflammatory homeostasis of arsenic-induced skin lesions.

Abstract

This study aimed to investigate the effect of N6-methyladenosine (m6 A) modification in modulating inflammatory homeostasis of arsenic (As)-induced skin lesions. Our bioinformatic analysis revealed abnormal expression of m6 A RNA methylation regulators and cytokines in the arsenic-exposed population. In human keratinocytes, arsenite increased the levels of m6 A methylation by upregulating the RNA methyltransferase like 3 (METTL3), mediating the disordered secretion of indicators that reflect inflammatory homeostasis (IL-6, IL-17, and IL-10). The indicators reflecting arsenic-induced skin lesions (Krt1 and Krt10) were also significantly elevated, which contributed to the occurrence of skin lesions. Our results also confirmed the association between METTL3 with inflammatory homeostasis and arsenic-induced skin lesions using arsenic-exposed human skin samples. In the arsenic-exposed group, the upregulation of METTL3 exacerbated the increase in cytokine levels (IL-6, IL-17, and IL-10), which was associated with the upregulation of keratins (Krt1 and Krt10). In addition, significant correlations among these factors corroborate the theoretical links. Finally, alteration of the m6 A levels via knockdown or enhancement of the METTL3 protein could antagonize or aggravate arsenite-induced imbalanced inflammatory homeostasis and human keratinocyte damage in HaCaT cells. Collectively, our study reveals some evidence that regulation of m6 A modification plays an important role in arsenic-induced skin lesions, which provide a new perspective on the mechanism of arsenite-induced imbalanced inflammatory homeostasis in the field of RNA epigenetics.