Interleukin 23 Levels Are Increased in Carotid Atherosclerosis

Abstract

793S troke is one of the major causes of death and disability worldwide. Approximately 85% of all strokes are ischemic, and 20% to 30% of these are caused by carotid atherosclerosis. Moderate-to high-grade carotid artery stenosis can be detected in 1% to 3% of adults, and the incidence increases with age. [1][2][3] Along with the degree of stenosis, inflammation and plaque composition are important in predicting the risk of clinical symptoms. 4 The atherosclerotic plaque is composed of infiltrating inflammatory cells (eg, monocytes/macrophages, T cells, and dendritic cells [DCs]), smooth muscle cells, and lipids. Plaques prone to rupture have thin fibrous caps and high-grade inflammation. The balance between pro-and anti-inflammatory mediators is therefore of major importance for the fate of the plaque and for the occurrence of adverse events. 5,6Background and Purpose-Interleukin (IL)-23 is a cytokine in the IL-12 family, mainly produced by antigen-presenting cells with a central role in inflammation. We hypothesize that IL-23 is also important in atherogenesis and investigate this in a population with carotid atherosclerosis. Methods-Plasma levels of IL-23 were measured in patients with carotid artery stenosis and in healthy controls. The mRNA levels of IL-23 and its receptor, IL-23R, were measured in atherosclerotic plaques, nonatherosclerotic vessels, peripheral blood mononuclear cells, and plasmacytoid dendritic cells. Results-Our findings were as follows: (1) patients with carotid atherosclerosis (n=177) had significantly raised plasma levels of IL-23 when compared with healthy controls (n=24) with particularly high levels in those with the most recent symptoms. (2) mRNA levels of IL-23 and IL-23R were markedly increased in carotid plaques (n=68) when compared with nonatherosclerotic vessels (n=8-10). Immunostaining showed colocalization to plaque macrophages. (3) Patients with carotid atherosclerosis had increased mRNA levels of both IL-23 and IL-23R in plasmacytoid dendritic cells, but not in peripheral blood mononuclear cells. (4) 14-16 Thus, patients with peripheral arterial disease have raised serum levels of IL-23, and increased IL-23 expression is seen in human carotid lesions.14,16 Zhang et al 17 showed that carriers of a polymorphism in the IL-23R gene, which also gave increased expression of IL-23R in peripheral blood mononuclear cells (PBMCs), had increased risk of coronary artery disease. However, decreased IL-23 in PBMCs from patients with coronary artery disease has also been reported. 18 In a mouse model of ischemic stroke, IL-23 levels were upregulated in both the circulation and in the brain. 15 However, the role for IL-23 in atherosclerosis is still unclear.In this study, we examined the expression of IL-23 in patients with carotid atherosclerosis both systemically and within the atherosclerotic plaque as well as its relation to adverse events during follow-up. We also examined the effect of IL-23 in PBMCs and monocytes from patients with carotid atherosclerosis and healthy controls. Mat...

Roles and Mechanisms of Interleukin-12 Family Members in Cardiovascular Diseases: Opportunities and Challenges

“…Induce and promote th17 differentiation IL-27 alone has no apparent stimulatory properties, collaboration with other ILs promote or inhibit T cell differentiation and proliferation Promote Treg activity, suppress the Teff cell (Th1, and Th17 ) activity Ma and Trinchieri, 2001;Kastelein et al, 2007;Collison and Vignali, 2008;Vignali et al, 2008;Cox et al, 2011;Vignali and Kuchroo, 2012;Wojno and Hunter, 2012;Sun et al, 2015 Regulation of inflammation Except inflammatory environment induced by DOX or Ang II, all play pro-inflammatory role Always play a proinflammatory roles, no anti-inflammatory effects had been reported Not only play an anti-inflammatory role, but also play a proinflammatory effects, may be associated with inflammatory microenvironment Always relieves the inflammatory response Davenport and Tipping, 2003;Vignali and Kuchroo, 2012;Jin et al, 2012;Koltsova et al, 2012;Li et al, 2012;Yan et al, 2012;Jääskeläinen et al, 2013;Abbas et al, 2015;Subramanian et al, 2015;Sun et al, 2015;Andrews et al, 2016;Tao et al, 2016;Hu et al, 2016;Gregersen et al, 2017;Fatkhullina et al, 2018;Ye et al, 2018b;Jia et al, 2019;Liu et al, 2019;Vargas-Alarcón et al, 2019;Ye et al, 2019 family members have significantly higher levels of expression in patients with atherosclerosis and coronary artery disease, and are closely related to the progression of these diseases.…”

The role of cytokines in the development of atherosclerosis

“…This complicates the interpretation of in vivo phenotypes of mice with the knockouts of individual subunits. The observed positive correlation between CVD and the levels of IL-12 and IL-23 in patients' blood suggests proatherogenic function of these cytokines [69]. IL-12 has been shown to act as a proatherogenic molecule in animal models, since the size of atherosclerotic lesions in Il12 −/− Apoe −/− mice was considerably smaller than in the control group [70].…”

Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis

“…Carotid plaques used for immunohistochemistry (IHC) and fluorescence microscopy were obtained from patients with carotid stenosis (47). Signed informed consent for participation in the study was obtained from all individuals.…”