METTL3/ALKBH5-Mediated N6-Methyladenosine Modification Drives Macrophage M1 Polarization via the SLC15A3-TASL-IRF5 Signaling Axis in Psoriasis.

ABSTRACT: Impaired N6-methyladenosine (m⁶A) modification has been implicated in regulating various inflammatory diseases, but its role in psoriasis remains unclear. Here, m⁶A modification and its methyltransferase METTL3 are revealed to be upregulated in psoriatic macrophages, while the demethylase ALKBH5 is downregulated. Conditional knockout of Mettl3 in macrophages alleviated psoriasis-like symptoms in mice, whereas knockout of Alkbh5 exacerbated them. Both in vivo and in vitro, Mettl3 deficiency inhibited IMQ-induced M1 macrophage polarization, while Alkbh5 deficiency promoted M1 polarization. The regulation of macrophage polarization by m⁶A is likely mediated by targeting Slc15a3. SLC15A3 enhances the recruitment of TASL, a recently identified endolysosomal IRF5

SUBMITTER: Huang T 

PROVIDER: S-EPMC12462922 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature