Macrophage-specific expression of IL-37 in hyperlipidemic mice attenuates atherosclerosis
The Journal of Immunology, 2017•journals.aai.org
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 …
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 …
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 (eg, IL-1B, IL-6, and IL-12) and secreted protein production (eg, 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 Ldlr−/− 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.
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