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

Abstract

<p id="P3">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. </p><p id="P4">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. </p><p id="P5"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/e0237bb5-72f3-4526-903e-c4d1ae317e88/PubMedCentral/image/nihms-1510832-f0001.jpg"/> </div> </p>