Mettl14 mediates the inflammatory response of macrophages in atherosclerosis through the NF-κB/IL-6 signaling pathway

Abstract

The inflammatory response of macrophages has been reported to play a critical role in atherosclerosis. The inflammatory state of macrophages is modified by epigenetic reprogramming. m6A RNA methylation is an epigenetic modification of RNAs. However, little is known about the potential roles and underlying mechanisms of m6A modification in macrophage inflammation. Herein, we showed that the expression of the m6A modification “writer” Mettl14 was increased in coronary heart disease and LPS-stimulated THP-1 cells. Knockdown of Mettl14 promoted M2 polarization of macrophages, inhibited foam cell formation and decreased migration. Mechanistically, the expression of Myd88 and IL-6 was decreased in Mettl14 knockdown cells. Through m6A modification, Mettl14 regulated the stability of Myd88 mRNA. Furthermore, Myd88 affected the transcription of IL-6 via the distribution of p65 in nuclei rather than directly regulating the expression of IL-6 through m6A modification. In vivo, Mettl14 gene knockout significantly reduced the inflammatory response of macrophages and the development of atherosclerotic plaques. Taken together, our data demonstrate that Mettl14 plays a vital role in macrophage inflammation in atherosclerosis via the NF-κB/IL-6 signaling pathway, suggesting that Mettl14 may be a promising therapeutic target for the clinical treatment of atherosclerosis.

m6A methylation: a process reshaping the tumour immune microenvironment and regulating immune evasion

“…METTL3 facilitates M1 macrophage polarization through m 6 A-mediated augmentation of STAT1 expression [ 211 ]. METTL14 deficiency induces M2 macrophage polarization and decreases Myd88 and IL-6 levels due to loss of m 6 A modification [ 212 ]. IGF2BP2 targets methylated TSC1 to induce macrophage polarization from the M1 to the M2 phenotype and alleviate inflammation [ 213 ].…”

Epigenetic Regulation of Macrophage Polarization in Cardiovascular Diseases

“…Further, METTL3 and METTL14 KO inhibits M1 but not M2 macrophage polarization. Thus, these loci serve as potential anti-inflammatory targets [ 80 , 81 ].…”

Crosstalk among N6-methyladenosine modification and RNAs in central nervous system injuries

“…Studies have indicated that the NF-κB signaling pathway might be the key target. It has been shown that METTL14 played a vital role in macrophage inflammation in atherosclerosis via the NF-κB/IL-6 signaling pathway ( Zheng et al, 2022 ). Furthermore, METTL3 participated in sympathetic neural remodeling post-myocardial infarction (MI) via the NF-κB pathway and reactive oxygen species (ROS) production.…”