Interleukin-37 attenuates aortic valve lesions by inhibiting m6A-mediated IRAK-M degradation

Abstract

Aims Calcific aortic valve disease (CAVD) has become an increasingly important global medical problem without effective pharmacological intervention. Accumulating evidence indicates that aortic valve calcification is driven by inflammation. Interleukin-1 receptor-associated kinase M (IRAK-M) is a well-known negative regulator of inflammation, but its role in CAVD remains unclear. Methods and Results Here, we stimulated aortic valve interstitial cells (AVICs) with low-dose lipopolysaccharide (LPS) to mimic the inflammatory response in aortic valve calcification and observed the expression pattern of IRAK-M. Furthermore, we generated IRAK-M-/- mice to explore the effect of IRAK-M deficiency on the aortic valve in vivo. Additionally, overexpression and knockdown experiments were performed to verify the role of IRAK-M in AVICs. MeRIP‒qPCR was used to detect the N6-methyladenosine (m6A) level of IRAK-M, and recombinant interleukin (IL)-37-treated AVICs were used to determine the regulatory relationship between IL-37 and IRAK-M. We found that IRAK-M expression was upregulated in the early stages of inflammation as part of a negative feedback mechanism to modulate the immune response. However, persistent inflammation increased overall m6A levels, ultimately leading to reduced IRAK-M expression. In vivo, IRAK-M-/- mice exhibited a propensity for aortic valve thickening and calcification. Overexpression and knockdown experiments showed that IRAK-M inhibited inflammation and osteogenic responses in AVICs. In addition, IL-37 restored IRAK-M expression by inhibiting m6A-mediated IRAK-M degradation to suppress inflammation and aortic valve calcification. Conclusions Our findings confirm that inflammation and epigenetic modifications synergistically regulate IRAK-M expression. Moreover, IRAK-M represents a potential target for mitigating aortic valve calcification. Meanwhile, IL-37 exhibited inhibitory effects on CAVD development both in vivo and in vitro, giving us hope that CAVD can be treated with drugs rather than surgery.