دورية أكاديمية
CCL18 aggravates atherosclerosis by inducing CCR6-dependent T-cell influx and polarization.
العنوان: | CCL18 aggravates atherosclerosis by inducing CCR6-dependent T-cell influx and polarization. |
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المؤلفون: | Singh A; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands., Kraaijeveld AO; Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands.; Department of Cardiology, University Medical Center Utrecht, Utrecht, Netherlands., Curaj A; Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany., Wichapong K; Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands., Hammerich L; Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany., de Jager SCA; Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands.; Department of Experimental Cardiology, University Medical Center Utrecht, Utrecht, Netherlands., Bot I; Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands., Atamas SP; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States., van Berkel TJC; Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands., Jukema JW; Department of Cardiology, Leiden University Medical Center (LUMC), Leiden, Netherlands., Comerford I; Centre for Molecular Pathology, School of Molecular & Biomedical Science, University of Adelaide, Adelaide, SA, Australia., McColl SR; Centre for Molecular Pathology, School of Molecular & Biomedical Science, University of Adelaide, Adelaide, SA, Australia., Mees B; Department of Surgery, Maastricht University, Maastricht, Netherlands., Heemskerk JWM; Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands., Nicolaes GAF; Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands., Hackeng T; Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands., Liehn EA; Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany., Tacke F; Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany.; Department of Hepatology & Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany., Biessen EAL; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands.; Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands. |
المصدر: | Frontiers in immunology [Front Immunol] 2024 May 13; Vol. 15, pp. 1327051. Date of Electronic Publication: 2024 May 13 (Print Publication: 2024). |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: [Lausanne : Frontiers Research Foundation] |
مواضيع طبية MeSH: | Atherosclerosis*/immunology , Atherosclerosis*/metabolism , Receptors, CCR6*/metabolism , Receptors, CCR6*/genetics , Chemokines, CC*/metabolism , Chemokines, CC*/genetics, Animals ; Humans ; Mice ; Disease Models, Animal ; Mice, Inbred C57BL ; Jurkat Cells ; Plaque, Atherosclerotic/immunology ; Mice, Knockout ; Male ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Th17 Cells/immunology ; Th17 Cells/metabolism ; Female ; Mice, Knockout, ApoE |
مستخلص: | Introduction: The CC chemokine ligand 18 (CCL18) is a chemokine highly expressed in chronic inflammation in humans. Recent observations of elevated CCL18 plasma levels in patients with acute cardiovascular syndromes prompted an investigation into the role of CCL18 in the pathogenesis of human and mouse atherosclerosis. Methods and Results: CCL18 was profoundly upregulated in ruptured human atherosclerotic plaque, particularly within macrophages. Repeated administration of CCL18 in Western-type diet-fed ApoE -/- mice or PCSK9 mut -overexpressing wild type (WT) mice led to increased plaque burden, enriched in CD3 + T cells. In subsequent experimental and molecular modeling studies, we identified CCR6 as a functional receptor mediating CCL18 chemotaxis, intracellular Ca 2+ flux, and downstream signaling in human Jurkat and mouse T cells. CCL18 failed to induce these effects in vitro in murine spleen T cells with CCR6 deficiency. The ability of CCR6 to act as CCL18 receptor was confirmed in vivo in an inflammation model, where subcutaneous CCL18 injection induced profound focal skin inflammation in WT but not in CCR6 -/- mice. This inflammation featured edema and marked infiltration of various leukocyte subsets, including T cells with a Th17 signature, supporting CCR6's role as a Th17 chemotactic receptor. Notably, focal overexpression of CCL18 in plaques was associated with an increased presence of CCR6 + (T) cells. Discussion: Our studies are the first to identify the CCL18/CCR6 axis as a regulator of immune responses in advanced murine and human atherosclerosis. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Singh, Kraaijeveld, Curaj, Wichapong, Hammerich, de Jager, Bot, Atamas, van Berkel, Jukema, Comerford, McColl, Mees, Heemskerk, Nicolaes, Hackeng, Liehn, Tacke and Biessen.) |
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فهرسة مساهمة: | Keywords: Th17; cardiovascular; chemokines; chemotaxis; inflammation; plaque |
المشرفين على المادة: | 0 (Receptors, CCR6) 0 (Chemokines, CC) 0 (CCL18 protein, human) 0 (CCR6 protein, mouse) 0 (CCR6 protein, human) |
تواريخ الأحداث: | Date Created: 20240529 Date Completed: 20240529 Latest Revision: 20240530 |
رمز التحديث: | 20240530 |
مُعرف محوري في PubMed: | PMC11131369 |
DOI: | 10.3389/fimmu.2024.1327051 |
PMID: | 38807599 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1664-3224 |
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DOI: | 10.3389/fimmu.2024.1327051 |