WTAP-m6A-ALOX15 axis mediates dendritic cells-keratinocytes interaction involved in lipid metabolism disorders to drive atopic dermatitis

Background: The pathogenesis of atopic dermatitis (AD) involves a complex immune regulatory network between dendritic cells (DCs) and keratinocytes (KCs). Recent studies have found that N6-methyladenosine (m6A) RNA modification modulates immune regulation and skin barrier homeostasis, but it is unclear whether it participates in AD through the DCs-KCs interaction crosstalk. This study aimed to investigate whether m6A modification contributes to the pathological features of atopic dermatitis by regulating ALOX15 expression in dendritic cells. Methods: We integrated bioinformatics analysis with clinical sample validation to examine ALOX15 expression in AD skin lesions. Methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) was performed to quantify changes in the m6A methylation of ALOX15. Three co-culture systems using primary mouse bone marrow-derived DCs (BMDCs), DC 2.4 cells, and primary mouse KCs were established to investigate how ALOX15 mediates DC activation and influences the biological behavior of KCs. Results: ALOX15 expression was significantly upregulated in DCs from AD lesions. Mechanistically, WTAP-mediated m6A modification enhanced ALOX15 expression, prompting DCs activation and inflammatory factor secretion. Co-culture experiments demonstrated that ALOX15-overexpressing DCs secreted elevated levels of inflammatory factors and arachidonic acid metabolites (LTB4, 12-HETE, and 15-HETE), leading to abnormal KCs' differentiation, proliferation disorders, and lipid metabolism disorders, which are characteristic phenotypic changes of AD. Conclusions: Our findings underscore the critical role of the WTA-m6A-ALOX15 axis in regulating DCs-KCs interactions in AD, providing new theoretical foundations and potential intervention targets for future interventions.