Abstract
IL-37 is a newly discovered inflammatory factor. However, the protective effect and underlying mechanisms of IL-37 on atherosclerosis remain unclear. In the present study, IL-37 was used for intraperitoneal injection in diabetic ApoE-/- mice caused by streptozotocin. High glucose (HG)/ox-LDL was used to stimulate THP-1 original macrophage followed by IL-37 pretreatment in vitro. The atheromatous plaque area, oxidative stress and inflammation levels in ApoE-/- mice were evaluated, and the level of macrophage ferroptosis was detected in vivo and in vitro. It was identified that IL-37 treatment significantly decreased plaque area in diabetic ApoE-/- mice. IL-37 not only improved blood lipid levels in mice, but also reduced serum levels of inflammatory factors including IL-1β and IL-18. Furthermore, IL-37 increased GPX4 and nuclear factor erythroid 2-related factor 2 (NRF2) in the aorta of diabetic mice. In vitro experiment revealed that IL-37 inhibited HG/ox-LDL-induced ferroptosis in macrophages, as evidenced by improved cell membrane oxidation, reduced malondialdehyde production and increased GPX4 expression. Moreover, it was also found that IL-37 enhanced the nuclear translocation of NRF2 in macrophages, while ML385, a specific NRF2 inhibitor, significantly attenuated the protective effect of IL-37 on macrophage ferroptosis caused by HG/ox-LDL. In conclusion, IL-37 suppressed macrophage ferroptosis to attenuate atherosclerosis progression via activating the NRF2 pathway.