Leukocyte-Derived Interleukin 10 Is Required for Protection Against Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice

Abstract

Background— Atherosclerosis is an immunoinflammatory disease. Here we examined the role of leukocyte-derived interleukin 10 (IL-10) on advanced atherosclerosis development in low-density lipoprotein receptor knockout (LDLr−/−) mice. Methods and Results— Bone marrow cells harvested from C57BL/6 IL-10−/− and IL-10+/+ mice were transplanted into irradiated male LDLr−/− mice. Four weeks after transplantation, mice were fed a high-fat cholate-free diet for 14 weeks. Despite no differences in weights, serum total, and HDL-cholesterol levels between the 2 groups, IL-10 deficiency in leukocytes induced a >2-fold increase in lesion development in the thoracic aorta compared with controls. We also found a significant 35% increase in aortic root lesion area of IL-10−/− mice compared with IL-10+/+ mice. Furthermore, IL-10 deficiency led to a marked increase in lymphocyte and macrophage accumulation associated with a significant reduction in collagen accumulation. Finally, transfer of IL-10−/− splenocytes to LDLr−/− mice resulted in a 3-fold increase in lesion size in the aortic sinus compared with mice transplanted with IL-10+/+ splenocytes. Conclusion— IL-10 expressed by leukocytes prevents exaggerated advanced atherosclerosis development and plays a critical role in modulation of cellular and collagen plaque composition, at least in part, through a modulation of the systemic immune response.

Both STAT3 activation and cholesterol efflux contribute to the anti-inflammatory effect of apoA-I/ABCA1 interaction in macrophages

“…Selective silencing of STAT3 in mouse macrophages and neutrophils increases susceptibility to endotoxic shock and promotes chronic entercolitis (27,43). The antiinflammatory cytokine IL-10 suppresses the production of inflammatory cytokines in macrophages through STAT3, and IL-10 knockout mice have chronic inflammation and increased atherosclerosis (26,44). Here we found that activating STAT3 without cholesterol efflux by the interaction of apoA-I/ABCA1 significantly inhibited proinflammatory cytokine expression in macrophages.…”

Allograft inflammatory factor-1 augments macrophage phagocytotic activity and accelerates the progression of atherosclerosis in ApoE−/− mice

“…Another possible explanation may be that AIF-1 overexpression biases the immune response from Th1 to Th2 as we have demonstrated in in vitro experiments (14) and in the trinitrobenzene sulphonateinduced colitis model in mice (15). Since atherosclerosis is aggravated in the Th1 condition, the Th2-biased immune deviation (elevation of IL-6 and IL-10 levels) may exert regulatory influences on atherogenesis in the AIF-1 Tg environment (32)(33)(34)(35)(36). However, AIF-1 transfectants also produce IL-12, a pro-atherogenic factor, upon stimulation with LPS (14).…”

Thematic review series: The Immune System and Atherogenesis. Immune function in atherogenesis

“…This is exemplified in recent murine atherosclerosis studies on IFN-␥ deficiency in atherosclerosis in the LDL receptordeficient mouse (40). Lesion phenotype is dramatically changed with modulation of IL-10 signaling and attenuation or alteration of TGF ␤ signaling (42,43,47,49).…”

“…When LDL receptor-deficient mice are transplanted with bone marrow overexpressing IL-10 in T-cells, atherosclerosis is reduced (42). In contrast, the transplantation of IL-10-deficient bone marrow into LDL receptor-deficient mice led to a marked increase in lesion development at several sites, and these lesions were rich in macrophages and lymphocytes (43). Nuclear factor B (NF-B) mediates many proinflammatory effects.…”