Abstract 13453: Macrophage-driven Expression of IL-37 Protects Against Atherosclerosis
As the most prominent cell type in the pathogenesis of atherosclerosis, macrophages are the first cells to infiltrate into the intima where they induce inflammatory events that further exacerbate the disease. We have found recently that the human protein IL-37, a relatively unknown member of the IL-1 family of cytokines with no known mouse homolog, has potent anti-inflammatory activities. Accordingly, we sought to determine if macrophage-specific expression of IL-37 would be effective in curbing atherosclerosis via its ability to reduce the production of pro-inflammatory cytokines, reduce transmigration, and to regulate the accumulation of lipids in mouse bone marrow-derived macrophages (BMDM), ultimately proving to reduce the development of atherosclerosis in a mouse model of the disease. We achieved robust and long-term expression of IL-37 using a macrophage-specific retroviral overexpression system utilizing the CD68 promoter in mouse BMDMs via transduction of hematopoietic stem cells (HSC). Cytokine expression was measured by antibody array as well as RT-qPCR, transmigration of transduced BMDM was measured using a transwell filter assay, and lipid homeostasis by cholesterol uptake as well as efflux. The mouse study was accomplished through bone marrow transplantation (BMT) of transduced wt HSC (IL-37 vs GFP ctl, N=14) into irradiated ldlr-/- mice, with subsequent induction of atherosclerosis development over 10 weeks of HFD-feeding. IL-37 expression reduced the production of pro-inflammatory cytokine transcript and protein, reduced macrophage transmigration, as well improved macrophage cholesterol homeostasis. In vivo, mice that received IL-37-transduced HSC transplants showed significantly less plaque formation than mice that received GFP-transduced control HSCs. The potent anti-inflammatory as well as anti-atherogenic properties of IL-37 make it an attractive target for possible future therapy against atherosclerosis as well as other inflammatory conditions.
Author Disclosures: S. McCurdy: None. Y. Baumer: None. E. Toulmin: None. W. Boisvert: None.
- © 2014 by American Heart Association, Inc.