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 (m 6 A) modification in modulating inflammatory homeostasis of arsenic (As)-induced skin lesions. Our bioinformatic analysis revealed abnormal expression of m 6 A RNA methylation regulators and cytokines in the arsenic-exposed population. In human keratinocytes, arsenite increased the levels of m 6 A methylation by upregulating the RNA methyltransferase like 3 (METTL3), mediating the disordered secretion of indicators that reflect inflammatory homeostasis . 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 m 6 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 m 6 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.arsenic, imbalanced inflammatory homeostasis, N 6 -methyladenosine, skin lesions 1 | INTRODUCTION Arsenic (As), a natural element, is widely distributed in the environment. Arsenic exposure occurs primarily through ingestion of contaminated water or food and inhalation of contaminated air. 1,2 Arsenicosis is a multi-systemic disease that involves the digestive, cardiovascular, neural, and cutaneous systems, [3][4][5] which drastically impacts the quality of life and survival of patients and is a worldwide public health priority. A major target organ of As is the skin. The early manifestation of arsenic exposure and toxicity is skin lesions, including hyperkeratosis, hypopigmentation, and hyperpigmentation. 6 Immune dysfunction is an important pathogenesis mechanism of arseniasis. One of the main manifestations is an imbalanced inflammatory homeostasis. 7 Previous studies have confirmed that arsenicexposure can cause injury by triggering imbalanced inflammatory homeostasis in coal-burning As-exposed human and rats. This occurs by interfering with the secretion of pro-inflammatory and anti-inflammatory cytokines (IL-10) to disrupt the differentiation

Research Progress of m6A RNA Methylation in Skin Diseases

“…Further experiments found that arsenic promoted m 6 A methylation by up-regulating METTL3 to increase the secretion of inflammatory factors including interleukin-(IL-) 6, IL-17, and IL-10 in human keratinocytes. Keratin 1 (KRT1) and keratin 10 (KRT10) reflecting skin injury were also significantly increased [34]. Another study demonstrated that METTL14 facilitated global genome repair (GGR) by regulating m 6 A RNA methylation-mediated DNA damage-binding protein 2 (DDB2) translation and inhibits ultraviolet B-(UVB-) induced skin tumorigenesis.…”

m<sup>6</sup>A methylation in cellular senescence of age-associated diseases

“…In regard to anti-inflammatory factors, m 6 A can modulate cytokines through the regulation of the p38 and MAPK inflammatory signalling pathways under METTL3 modification. Elevated METTL3 in human keratinocytes specifically regulates inflammatory responses by upregulating m 6 A levels to induce increased secretion of the anti-inflammatory cytokine IL-10 [105] . Given that anti-inflammatory cytokines can interact with proinflammatory cytokines to influence the SASP-induced inflammatory response and cellular senescence [ 106 , 107 ] , there is some evidence of a potential role for m 6 A in cellular senescence by targeting the production of pro- and anti-inflammatory factors.…”