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

ABSTRACT: BACKGROUND:Interleukin-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 RESULTS:We used heterozygous Ldlr-/-Il23reGFP/WT knock-in mice to identify IL-23R-expressing cells by flow cytometry and homozygous Ldlr-/-Il23reGFP/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-?, 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. CONCLUSIONS:These 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.

SUBMITTER: Engelbertsen D

PROVIDER: S-EPMC6015431 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Engelbertsen Daniel D Depuydt Marie A C MAC Verwilligen Robin A F RAF Rattik Sara S Levinsohn Erik E Edsfeldt Andreas A Kuperwaser Felicia F Jarolim Petr P Lichtman Andrew H AH

Journal of the American Heart Association 20180404 8

<h4>Background</h4>Interleukin-23 (IL-23) has been implicated in inflammatory and autoimmune diseases by skewing CD4<sup>+</sup> 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.<h4>Methods and results</h4>We used heterozygous <i>Ldlr</i><sup><i>-/-</i></sup><i>Il23r</i><sup><i>e</i></sup><sup>< ...[more]

PMID: 29618473

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Project description:Atherosclerosis is a major cause of heart attack and stroke. Inflammation plays a critical role in the development of atherosclerosis. Since the cytoplasmic adaptor molecule TRAF3IP2 (TRAF3-Interacting Protein 2) plays a causal role in various autoimmune and inflammatory diseases, we hypothesized that TRAF3IP2 mediates atherosclerotic plaque development.TRAF3IP2/ApoE double knockout (DKO) mice were generated by crossing TRAF3IP2(-/-) and ApoE(-/-) mice. ApoE(-/-) mice served as controls. Both DKO and control mice were fed a high-fat diet for 12 weeks. Plasma lipids were measured by ELISA, atherosclerosis by en face analysis of aorta and plaque cross-section measurements at the aortic valve region, plaque necrotic core area, collagen and smooth muscle cell (SMC) content by histomorphometry, and aortic gene expression by RT-qPCR.The plasma lipoprotein profile was not altered by TRAF3IP2 gene deletion in ApoE(-/-) mice. While total aortic plaque area was decreased in DKO female, but not male mice, the plaque necrotic area was significantly decreased in DKO mice of both genders. Plaque collagen and SMC contents were increased significantly in both female and male DKO mice compared to respective controls. Aortic expression of proinflammatory cytokine (Tumor necrosis factor ?, TNF?), chemokine (Chemokine (C-X-C motif) Ligand 1, CXCL1) and adhesion molecule (Vascular cell adhesion molecule 1, VCAM1; and Intercellular adhesion molecule 1, ICAM1) gene expression were decreased in both male and female DKO mice. In addition, the male DKO mice expressed markedly reduced levels of extracellular matrix (ECM)-related genes, including TIMP1 (Tissue inhibitor of metalloproteinase 1), RECK (Reversion-Inducing-Cysteine-Rich Protein with Kazal Motifs) and ADAM17 (A Disintegrin And Metalloproteinase 17).TRAF3IP2 plays a causal role in atherosclerotic plaque development and vulnerability, possibly by inducing the expression of multiple proinflammatory mediators. TRAF3IP2 could be a potential therapeutic target in atherosclerotic vascular diseases.

Dataset Information

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

Publications

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

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