IL‑37 suppresses macrophage ferroptosis to attenuate diabetic atherosclerosis via the NRF2 pathway

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.

The dance of macrophage death: the interplay between the inevitable and the microenvironment

“…Significantly, IL-37 can mitigate ferroptosis-associated oxidative stress and Nrf2 inhibition. IL-37 enhances cellular viability and promotes the nuclear translocation of Nrf2 in THP-1 macrophages treated with oxLDLs ( 182 ). Long non-coding RNA lnc-MRGPRF-6:1 is another type of molecule that can contribute to foam cell ferroptosis.…”

The role of ferroptosis in diabetic cardiovascular diseases and the intervention of active ingredients of traditional Chinese medicine

“…Iron overload and ferroptosis in macrophages accelerate AS progression (Ma et al, 2022). Research by Xu et al (Xu et al, 2023) demonstrated that inhibiting macrophage ferroptosis through the NRF2 pathway significantly delayed the development of AS. A study by Bai et al (Bai et al, 2020) showed that the inhibitor of ferroptosis ferrostatin-1 could alleviate AS injury in ApoE −/− mice that were fed a high-fat diet.…”

Role of IL-1 Family Cytokines IL-36, IL-37, IL-38 in Osteoarthritis and Rheumatoid Arthritis: A Comprehensive Review

“… 31 High glucose (HG)/ox‑LDL stimulation and IL‑37 stimulation inhibited HG/ox‑LDL‑induced ferroptosis in macrophages, including improved cell membrane oxidation, decreased malondialdehyde expression, up-regulated glutathione peroxidase 4 (GPX4) expression and nuclear translocation of NRF2. 32 On the contrary, addition of NRF2 inhibitor suppressed effects of IL‑37 on macrophages ferroptosis. When WT mice were infected with A/California/07/2009 (H1N1) and then were injected with IL-37, expression of macrophage-related pro-inflammatory cytokines MCP-1, IL-1β, MIP-1α, MIP-1β, IFN-γ, RANTES was reduced in the lung.…”