Epidermal METTL1-Mediated m7G Modification Drives Psoriatic Inflammation by Stabilizing Bdkrb1 and Orchestrating Neutrophil Recruitment.

The functional significance of RNA modifications, specifically N7-methylguanosine (m7G), in inflammatory conditions such as psoriasis remains not fully elucidated. This study demonstrates that methyltransferase-like 1 (METTL1), an m7G methyltransferase, is significantly upregulated in epidermal keratinocytes of human psoriatic lesions and imiquimod (IMQ)-induced murine models. Utilizing mice with an inducible keratinocyte-specific Mettl1 deletion (Mettl1fl/flKrt14-CreERT2), the research reveals significantly attenuated psoriasiform inflammation and decreased neutrophil infiltration relative to Mettl1fl/fl counterparts. Mechanistically, METTL1 drives inflammation by augmenting Bdkrb1 mRNA stability through m7G modification. This stabilization leads to elevated bradykinin receptor B1 (BDKRB1) protein expression, which activates the p38 mitogen-activated protein kinase (MAPK) pathway in keratinocytes, promoting the secretion of key proinflammatory C-X-C motif chemokine ligand (CXCL) chemokines and robust neutrophil chemotaxis. Crucially, both in vivo genetic BDKRB1 overexpression and pharmacological BDKRB1 activation successfully rescue the attenuated inflammatory phenotype in Mettl1-deficient mice, firmly validating this specific signaling cascade. Conversely, pharmacological inhibition of the METTL1-BDKRB1 axis effectively mitigates psoriasiform inflammation. Collectively, these data establish that METTL1 modulates psoriasis by fostering p38-dependent chemokine production and neutrophil recruitment, identifying the METTL1-BDKRB1 axis as a novel therapeutic target.