Huang Tao, Chen Shijun, Ding Ke, Yuan Liyan, Lv Weiqi, Chen Kechen, Liu Yuchen, Ma Dongzhao, Zhang Xin, Wang Xiaobo, Luo Guanzheng, Yang Bin, Lin Ying, Rong Zhili
Dermatology Hospital, Southern Medical University, Guangzhou, 510091, China.
Cancer Research Institute, School of Basic Medical Sciences, State Key Laboratory of Multi-organ Injury Prevention and Treatment, Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, Southern Medical University, Guangzhou, 510515, China.
Adv Sci (Weinh). 2025 Jul 18:e01408. doi: 10.1002/advs.202501408.
Impaired N6-methyladenosine (mA) modification has been implicated in regulating various inflammatory diseases, but its role in psoriasis remains unclear. Here, mA 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 mA is likely mediated by targeting Slc15a3. SLC15A3 enhances the recruitment of TASL, a recently identified endolysosomal IRF5 adaptor, which functions similarly to the IRF3 adaptors STING and MAVS at the endoplasmic reticulum (ER) and mitochondria, respectively, to augment IRF5 signaling via SLC15A4. The findings underscore the critical role of mA RNA modification in psoriasis pathogenesis and unveil a novel regulatory mechanism of TASL-IRF5 signaling through mA modification, suggesting potential new therapeutic targets for psoriasis treatment.
N6-甲基腺苷（m6A）修饰受损与多种炎症性疾病的调控有关，但其在银屑病中的作用仍不清楚。在此研究中，发现m6A修饰及其甲基转移酶METTL3在银屑病巨噬细胞中上调，而脱甲基酶ALKBH5下调。巨噬细胞中Mettl3的条件性敲除减轻了小鼠的银屑病样症状，而Alkbh5的敲除则加剧了这些症状。在体内和体外，Mettl3缺陷均抑制咪喹莫特（IMQ）诱导的M1巨噬细胞极化，而Alkbh5缺陷则促进M1极化。mA对巨噬细胞极化的调节可能是通过靶向Slc15a3介导的。SLC15A3增强了TASL的募集，TASL是最近发现的一种内溶酶体IRF5衔接蛋白，其功能分别类似于内质网（ER）和线粒体处的IRF3衔接蛋白STING和MAVS，通过SLC15A4增强IRF5信号传导。这些发现强调了m6A RNA修饰在银屑病发病机制中的关键作用，并揭示了通过mA修饰的TASL-IRF5信号传导的新调控机制，为银屑病治疗提示了潜在的新治疗靶点。
