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Atheroprotective immunity and interleukin-10 linked to reduced plaque stability and recurrent cardiovascular events

ABSTRACT: Atherosclerotic cardiovascular disease remains a major cause of death worldwide. Autoimmunity to low-density lipoprotein (LDL) has been implicated in the disease process and immunization with LDL components proposed as a preventive strategy. However, mechanisms of atheroprotective immunity remain insufficiently characterized. Two different T cell receptor transgenic mouse strains with T cells reactive against the LDL protein, apoB100 (BT1 and BT3) were crossbred with human APOB100-transgenic Ldlr-/- (HuBL) mice, and atherosclerosis was evaluated. In 52-week-old BT1xHuBL mice, a lower atherosclerotic burden was observed in the aorta, mirrored by reduced plasma cholesterol and elevated anti-apoB100 antibodies. BT3xHuBL mice also exhibited a decrease in aortic atherosclerosis; however, no reduction in plasma cholesterol levels was noted. Instead, type 1 regulatory T cell responses with interleukin (IL)-10 production were mounted. This response was associated with reduced collagen content and a lower stability index of the atherosclerotic lesions. In human carotid artery plaques, IL10 mRNA levels were negatively correlated with collagen expression, and IL-10 was found to inhibit collagen production in vascular smooth muscle cells. We conclude that atheroprotective apoB immunity elicits two distinct pathways: lipid-lowering immune reactions and local anti-inflammatory IL-10 production. Since the latter is associated with decreased plaque stability and cardiovascular events, treatments aimed at increasing IL-10 signaling over extended periods to reduce vascular inflammation need reconsideration.

ORGANISM(S): Mus musculus

PROVIDER: GSE283077 | GEO | 2025/07/30

REPOSITORIES: GEO

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Project description:Exciting discoveries related to IL-1R/TLR signaling in development of atherosclerosis plaque have triggered intense interest in the molecular mechanisms by which innate immune signaling modulates the onset and development of atherosclerosis. Previous studies have clearly shown the definitive role of proinflammatory cytokine IL-1 in the development of atherosclerosis. Recent studies have provided direct evidence supporting a link between innate immunity and atherogenesis. While it is still controversial about whether infectious pathogens contribute to cardiovascular diseases, direct genetic evidence indicates the importance of IL-1R/TLR signaling in atherogenesis. In this study, we examined the role of IRAK4 kinase activity in modified LDL-mediated signaling using bone marrow-derived macrophage as well as in vivo model of atherosclerosis. First, we found that the IRAK4 kinase activity was required for modified LDL-induced NFÎºB activation and expression of a subset of proinflammatory genes, but not for the activation of MAPKs in bonemarrow-derived macrophage. IRAK4 kinase inactive knock-in (IRAK4KI) mice were bred onto ApoE-/- mice to generate IRAK4KI/ApoE-/- mice. Importantly, the aortic sinus lesion formation was impaired in IRAK4KI/ApoE-/- mice compared to that in ApoE-/- mice. Furthermore, proinflammatory cytokine production was reduced in the aortic sinus region of IRAK4KI/ApoE-/- mice compared to that in ApoE-/- mice. Taken together, our results indicate that the IRAK4 kinase plays an important role in modified LDL-mediated signaling and the development of atherosclerosis, suggesting that pharmacological inhibition of IRAK4 kinase activity might be a feasible approach in the development of anti-atherosclerosis drugs. To identify global changes in gene expression, we examined gene expression profiles of macrophages from wild-type and IRAK4 kinase-inactive knock-in mice in response to acLDL stimulation using the Illumina microarray with probes for 23,000 transcripts. Bone marrow-derived macrophages from wild-type and IRAK4 kinase-inactive knock-in mice were treated with acLDL for 24 hours.

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Atheroprotective immunity and interleukin-10 linked to reduced plaque stability and recurrent cardiovascular events

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