Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis

Abstract

Atherosclerosis is an inflammatory vascular disease responsible for the first cause of mortality worldwide. Recent studies have clearly highlighted the critical role of the immunoinflammatory balance in the modulation of disease development and progression. However, the immunoregulatory pathways that control atherosclerosis remain largely unknown. We show that loss of suppressor of cytokine signaling (SOCS) 3 in T cells increases both interleukin (IL)-17 and IL-10 production, induces an antiinflammatory macrophage phenotype, and leads to unexpected IL-17–dependent reduction in lesion development and vascular inflammation. In vivo administration of IL-17 reduces endothelial vascular cell adhesion molecule–1 expression and vascular T cell infiltration, and significantly limits atherosclerotic lesion development. In contrast, overexpression of SOCS3 in T cells reduces IL-17 and accelerates atherosclerosis. We also show that in human lesions, increased levels of signal transducer and activator of transcription (STAT) 3 phosphorylation and IL-17 are associated with a stable plaque phenotype. These results identify novel SOCS3-controlled IL-17 regulatory pathways in atherosclerosis and may have important implications for the understanding of the increased susceptibility to vascular inflammation in patients with dominant-negative STAT3 mutations and defective Th17 cell differentiation.

Aortic VCAM‐1: an early marker of vascular inflammation in collagen‐induced arthritis

“…Moreover, its role in vascular dysfunction such as atherosclerosis is controversial 45, 46, 47. According to Madhur et al ., IL‐17A is necessary to induce superoxide vascular production in response to a high fat diet in ApoE −/− mice 48.…”

IL-17A Influences Essential Functions of the Monocyte/Macrophage Lineage and Is Involved in Advanced Murine and Human Atherosclerosis

“…Atherosclerosis and its consequences (i.e., myocardial infarction and stroke) remain the major cause of morbidity and mortality in Western countries. Several studies have investigated the role of IL-17A in the development of atherosclerosis with partially controversial results (7)(8)(9)(10)(11)(24)(25)(26), which are at least partially based on the study design, neutralizing Ab versus bone marrow transfer experiments, on the type of diet, and on the location of the analysis of the atherosclerotic lesion. By contrast, the current study evaluated the role of IL-17A on advanced atherosclerotic lesions and its potential impact as a therapeutic target.…”

“…IL-17A is produced by various inflammatory cells, including T cells and macrophages, and modulates the expression of several proinflammatory molecules (TNF-a, IL-1b, and CCL2 [MCP-1]) and matrix metalloproteinases (5,7). Previously, our group and others (7)(8)(9)(10)(11) have shown that inhibition of IL-17A influenced atherosclerotic lesion development in mice with partially controversial results. Because the highest expression rates of IL-17A were observed in human carotid artery plaques derived from symptomatic patients with stroke or transient ischemic attack (12,13), IL-17A may be linked to vulnerability of human atherosclerotic lesions.…”

Emerging biomarkers and intervention targets for immune-modulation of atherosclerosis – A review of the experimental evidence

“…The role of Th17 in atherosclerosis is also debated as conflicting reports exist (30)(31)(32). In contrast to CD4 + T helper cells, CD8 + cytolytic T lymphocytes have not been extensively studied, even though CD8 + T cells are abundant in atherosclerotic plaques and they have been shown to be activated in hypercholesterolemic Apoe -/-mice (33).…”