P10 Lipid metabolism modulated by <i>N</i>6-methyladenosine modification governs neutrophil chemotaxis and skin immune homeostasis

Abstract Disruption of N6-methyladenosine (m6A) modification has been implicated in various inflammatory disorders; however, its role in the regulation of cutaneous inflammation remains poorly understood. In this study, we demonstrate that both m6A and its methyltransferase, METTL3, are significantly downregulated in keratinocytes associated with inflammatory skin diseases such as psoriasis and atopic dermatitis. Inducible deletion of Mettl3 in murine keratinocytes heightened susceptibility to cutaneous inflammatory responses, characterized by enhanced neutrophil recruitment and fatty acid metabolism rewiring. Importantly, we propose a model in which m6A modification stabilizes the mRNA of the lipid-metabolizing enzyme ELOVL6 via the m6A reader IGF2BP3. This stabilization reprogrammes fatty acid metabolism, resulting in decreased palmitic acid accumulation and, consequently, suppression of neutrophil chemotaxis during cutaneous inflammation. Our findings illuminate a previously unrecognized epithelial-intrinsic m6A modification-lipid metabolism axis that is crucial for maintaining epidermal and immune homeostasis, thereby providing a foundation for potential therapeutic strategies targeting m6A modulators to alleviate inflammatory skin disorders, including psoriasis and atopic dermatitis.