Macrophage-Specific Expression of IL-37 in Hyperlipidemic Mice Attenuates Atherosclerosis

Abstract

Atherosclerosis, the progressive buildup of plaque within arterial blood vessels, can lead to fatal downstream events, such as heart attack or stroke. A key event contributing to the development of atherosclerosis is the infiltration of monocytes and its associated inflammation, as well as the formation of lipid-laden macrophage foam cells within the vessel wall. IL-37 is recognized as an important anti-inflammatory cytokine expressed especially by immune cells. This study was undertaken to elucidate the role of macrophage-expressed IL-37 in reducing the production and effects of proinflammatory cytokines, preventing foam cell formation, and reducing the development of atherosclerosis. Expression of human IL-37 was achieved with a macrophage-specific overexpression system, using the CD68 promoter in mouse primary bone marrow-derived macrophages via retroviral transduction. Macrophage IL-37 expression in vitro resulted in decreased mRNA (e.g., IL-1B, IL-6, and IL-12) and secreted protein production (e.g., IL-6, M-CSF, and ICAM-1) of key inflammatory mediators. IL-37 expression also inhibited macrophage proliferation, apoptosis, and transmigration, as well as reduced lipid uptake, compared with controls in vitro. The in vivo effects of macrophage-expressed IL-37 were investigated through bone marrow transplantation of transduced hematopoietic stem cells into irradiated atherosclerosis-prone mice. After 10 wk on a high-fat/high-cholesterol diet, mice with IL-37-expressing macrophages showed reduced disease pathogenesis, which was demonstrated by significantly less arterial plaque development and systemic inflammation compared with control mice. The athero-protective effect of macrophage-expressed IL-37 has implications for development of future therapies to treat atherosclerosis, as well as other chronic inflammatory diseases.

Anti-Inflammatory Effect of IL-37-Producing T-Cell Population in DSS-Induced Chronic Inflammatory Bowel Disease in Mice

“…As shown in previous studies, IL-37-expressing cells exert protective effects on several established animal disease models [21,22]. Therefore, we examined whether IL-37-producing T-cells could improve the colitis activity in our DSS-induced mouse model.…”

IL-37 Gene and Cholesterol Metabolism: Association of Polymorphisms with the Presence of Hypercholesterolemia and Cardiovascular Risk Factors. The GEA Mexican Study

“…Recently, Li et al [ 31 ] reported that the IL-37 was highly expressed in the elderly T2DM patients, and that this expression correlated with the insulin resistance index, suggesting the association of this cytokine with insulin resistance and sensitivity. It has been reported that in vitro IL-37 expression reduces macrophage inflammation and migration and inhibits modified LDL uptake, suggesting an athero-protective role for macrophage-expressed IL-37 [ 32 ].…”

Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis

“…and LMC mice aged 12-17 weeks as described previously (57). For experiments involving MnCl 2 , portions of the macrophages were differentiated for 6 days and replated in the presence of 5 μM MnCl 2 .…”

“…Human and mouse macrophage capacity to efflux uptaken radioactive cholesterol toward standardized HDL and ApoA-1 was performed as described previously (57,58).…”