IL‐23R Deficiency Does Not Impact Atherosclerotic Plaque Development in Mice

Abstract

BackgroundInterleukin‐23 (IL‐23) has been implicated in inflammatory and autoimmune diseases by skewing CD4+ T helper cells towards a pathogenic Th17 phenotype. In this study we investigated the presence of IL‐23 receptor (IL‐23R)‐expressing cells in the atherosclerotic aorta and evaluated the effect of IL‐23R deficiency on atherosclerosis development in mice.Methods and ResultsWe used heterozygous Ldlr −/− Il23r e GFP / WT knock‐in mice to identify IL‐23R‐expressing cells by flow cytometry and homozygous Ldlr −/− Il23r e GFP / eGFP (Ldlr −/− Il23r −/−) mice to investigate the effect of lack of IL‐23R in atherosclerosis. We demonstrate the presence of relatively rare IL‐23R‐expressing cells in lymphoid tissue and aorta (≈0.1–1% IL23R+ cells of all CD45+ leukocytes). After 10 weeks on a high‐fat diet, production of IL‐17, but not interferon‐γ, by CD4+ T cells and other lymphocytes was reduced in Ldlr −/− Il23r −/− compared with Ldlr −/−controls. However, Ldlr −/− and Ldlr −/− Il23r −/− mice had equivalent amounts of aortic sinus and descending aorta lesions. Adoptive transfer of IL‐23R‐deficient CD4+ T cells to lymphopenic Ldlr −/− Rag1 −/− resulted in dramatically reduced IL‐17‐producing T cells but did not reduce atherosclerosis, compared with transfer of IL‐23R‐sufficient CD4+ T cells.ConclusionsThese data demonstrate that loss of IL‐23R does not affect development of experimental atherosclerosis in LDLr‐deficient mice, despite a role for IL‐23 in differentiation of IL‐17‐producing T cells.

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

“…Just as Table 4. Although IL-12 family Fairweather et al, 2003;Yang et al, 2011;Nyland et al, 2012;Jenke et al, 2014;Kong et al, 2014;Hu et al, 2014;Zha et al, 2015;Zhang et al, 2017;Miteva et al, 2017;Sesti-Costa et al, 2017;Ouyang et al, 2017;Xu et al, 2018 Zhou et al, 2001;Kempe et al, 2009;Correia et al, 2010;Lin et al, 2012;Khojasteh-Fard et al, 2012;Jin et al, 2012;Yong et al, 2013;Chistiakov et al, 2015;Abbas et al, 2015;A Shahi et al, 2015;Zykov et al, 2016;Opstad et al, 2016;Zhu et al, 2018;Rasa et al, 2018; Lee et al, 1999;Davenport and Tipping, 2003;Hauer et al, 2005;Koltsova et al, 2012;Hirase et al, 2013;Subramanian et al, 2015;Kan et al, 2016;Tao et al, 2016;Engelbertsen et al, 2018;Fatkhullina et al, 2018;Ryu et al, 2018;Huang et al, 2019;Huang et al, 2019;Wang et al, 2019;Jia et...…”

“…Therapy involving IL-23p19, a subunit of IL-23, had no significant effect on atherosclerosis development in ApoE-deficient mice, although inflammatory responses were reduced . Another study reported that there was no significant difference in atherosclerotic area between low-density lipoprotein receptor (LDLR) knockout mice and IL-23 + LDLR double-knockout mice, after they were all fed with high-fat diet (Engelbertsen et al, 2018). A recent study reported that deficiency of IL-23 significantly decreased IL-22 expression in ApoE-knockout mice, and also reduced expression of IL-22, thereby relieving the release of inflammatory substances, and thus alleviating the process of atherosclerosis (Fatkhullina et al, 2018).…”

“…Subramanian et al reported that granulocyte-macrophage colony stimulating factor (GM-CSF) up-regulates the expression of IL-23, which further promotes the differentiation of macrophages and atherosclerosis development (Subramanian et al, 2015). These studies suggest that IL-23 has a strong regulatory effect on inflammation mediated by a high-fat diet in both ApoE-knockout mice and LDL-R-knockout mice (Subramanian et al, 2015;Engelbertsen et al, 2018;Fatkhullina et al, 2018;Wang et al, 2019), while the special role of IL-23 in atherosclerotic progression is unclear and further studies are needed to clarify this aspect.…”

“…81760051 to YL). Lee et al, 1999;Davenport and Tipping, 2003;Hauer et al, 2005;Koltsova et al, 2012;Hirase et al, 2013;Wang et al, 2014;Subramanian et al, 2015;Tao et al, 2016;Gorzelak-Pabiś et al, 2017;Engelbertsen et al, 2018;Fatkhullina et al, 2018;Li et al, 2018;Ryu et al, 2018;Huang et al, 2019;Wang et al, 2019…”

An Interleukin-23-Interleukin-22 Axis Regulates Intestinal Microbial Homeostasis to Protect from Diet-Induced Atherosclerosis

“…In previous studies, systemic expression of IL-23 in a transgenic model induced an inflammatory phenotype and promoted various inflammatory diseases, predisposing to atherosclerosis (Wiekowski et al, 2001). Short-term IL-23 injections have been shown to increase apoptosis in plaques, likely acting in a GM-CSF dependent manner, and it was shown that early lesions could develop unperturbed in the absence of IL-23R (Engelbertsen et al, 2018; Subramanian et al, 2015). In our model genetic inactivation of IL-23 resulted in an increased number of apoptotic cells in atherosclerotic plaques, confirming that apoptosis in the plaque is tightly linked to atherosclerosis progression.…”