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      An interleukin-23- interleukin-22 axis regulates intestinal microbial homeostasis to protect from diet-induced atherosclerosis

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          Summary

          While commensal flora is involved in the regulation of immunity, the interplay between cytokine signaling and microbiota in atherosclerosis remains unknown. We found that interleukin (IL)-23 and its downstream target IL-22 restricted atherosclerosis by repressing pro-atherogenic microbiota. Inactivation of IL-23-IL-22 signaling led to deterioration of the intestinal barrier, dysbiosis and expansion of pathogenic bacteria with distinct biosynthetic and metabolic properties, causing systemic increase in pro-atherogenic metabolites such as lipopolysaccharide (LPS) and trimethylamine N-oxide (TMAO). Augmented disease in the absence of the IL-23-IL-22 pathway was mediated in part by pro-atherogenic osteopontin, controlled by microbial metabolites. Microbiota transfer from IL-23 deficient mice accelerated atherosclerosis, whereas microbial depletion or IL-22 supplementation reduced inflammation and ameliorated disease. Our work uncovers the IL-23-IL-22 signaling as a regulator of atherosclerosis that restrains expansion of pro-atherogenic microbiota, and argues for informed use of cytokine blockers to avoid cardiovascular side effects driven by microbiota and inflammation.

          eTOC blurb

          While anti-cytokine therapies show promising results in autoimmune diseases, its effects on cardiovascular disease development are not well understood. Fatkhullina and colleagues show that inactivation of IL-23-IL-22 signaling leads to deterioration of the intestinal barrier, expansion of pro-atherogenic bacteria and production of metabolites promoting macrophage activation and atherosclerosis.

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          Author and article information

          Journal
          9432918
          8591
          Immunity
          Immunity
          Immunity
          1074-7613
          1097-4180
          30 October 2018
          30 October 2018
          20 November 2018
          20 November 2019
          : 49
          : 5
          : 943-957.e9
          Affiliations
          [1 ]Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
          [2 ]Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20814,USA
          [3 ]Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
          [4 ]Proteomics and Metabolomics The Wistar Institute, Philadelphia, PA, 19104, USA
          [5 ]Bioinformatics Facilities, The Wistar Institute, Philadelphia, PA, 19104, USA
          [6 ]Department of Cellular and Molecular Medicine, Lerner Research Institute Cleveland Clinic, Cleveland, OH, 44195, USA
          [7 ]Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
          [9 ]Lead Contact and Corresponding Author
          Author notes

          Authors Contributions

          ARF, SIG and EKK designed the study and planned the experiments; ARF, IOP, TA and EKK performed the experiments. AD performed microbiota sequencing and analysis and contributed with critical reading of the manuscript. TA, JM, VT, JB and GT assisted with microbiota sequencing analysis; H-YT and AK performed metabolomics analysis; RV and PS performed Scanning Electron Microscopy. SIG and GT participated in data interpretation and manuscript writing. SH assisted with TMAO measurements, data interpretation and manuscript writing. ARF, SG and EKK wrote the manuscript with the input of all co-authors.

          Lead Contact and Corresponding Author: Ekaterina Koltsova, MD, PhD, Blood Cell Development and Function Program, Fox Chase Cancer Center, P2151, Ekaterina.Koltsova@ 123456fccc.edu , phone +1-215-728-3113
          Article
          PMC6257980 PMC6257980 6257980 nihpa1510832
          10.1016/j.immuni.2018.09.011
          6257980
          30389414
          79c7d5be-a4ad-44dd-a2d4-3acca2b082ec
          Categories
          Article

          myeloid cells,host-microbe interaction,microbiome,cytokines,inflammation,atherosclerosis,IL-22,IL-23

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