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

• Published in: The Journal of immunology (1950) Vol. 199; no. 10; pp. 3604 - 3613
• Main Authors: McCurdy, Sara, Baumer, Yvonne, Toulmin, Emma, Lee, Bog-Hieu, Boisvert, William A
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 15.11.2017
• Subjects: Animals; Apoptosis; Arteriosclerosis; Atherosclerosis; Atherosclerosis - immunology; Blood vessels; Bone marrow; Bone marrow transplantation; Cells, Cultured; Cholesterol; Cytokines; Cytokines - metabolism; Diet, High-Fat; Hematopoietic stem cells; Humans; Hyperlipidemias - immunology; Inflammation Mediators - metabolism; Inflammatory diseases; Intercellular adhesion molecule 1; Interleukin 1; Interleukin 12; Interleukin 6; Interleukin-1 - genetics; Interleukin-1 - metabolism; Macrophage colony-stimulating factor; Macrophages; Macrophages - immunology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; mRNA; Myocardial infarction; Organ Specificity; Pathogenesis; Rodents; Stem cell transplantation; Stem cells; Stroke; Transplantation
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1601907

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.