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Interleukin (IL)-23 and -22 Restrict Atherosclerosis by Repressing Pro-Atherogenic Microbiota, Study Shows

November 21, 2018

Dr. KoltsovaPHILADELPHIA (November 21, 2018) — Research from Fox Chase Cancer Center shows that IL-23 and IL22 cytokines modulate microbiota composition and impact diet-induced atherosclerosis. The paper, by Aliia Fatkhullina, MS, a graduate student at Fox Chase, and Ekaterina Koltsova, MD, PhD, assistant professor in the Blood Cell Development and FunctionProgram at Fox Chase, appears in the journal Immunity.

Cardiovascular disease is the leading cause of death in developed countries. Cancer patients and survivors have at least three-fold higher risk of cardiovascular disease. Inflammation and its mediators, cytokines, are implicated in both cardiovascular disease and cancer. It is generally believed that inhibiting inflammation would be beneficial in reducing the risk of these diseases.

“The expectation in the field was always that inactivation or neutralization of inflammatory cytokines, specifically IL-23, would suppress atherosclerosis progression, however we found that ablation of IL23 or its target IL22 strongly promoted inflammatory cardiovascular disease,” Koltsova said.

IL23 inhibitors have been used to treat various immune-mediated diseases, such as inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and others. Some human studies of IL-12/IL-23 inhibitors revealed major cardiovascular events, but they were regarded as unexpected side effects without any molecular explanation.

“Our results revealed unexpectedly that the absence of these proteins augments atherosclerosis due to expansion of intestinal bacteria capable of producing pro-atherogenic metabolites,” Koltsova said. “We found that IL23-IL22 cytokine signaling is required to control host-microbial interaction and prevent the emergence of pro-atherogenic metabolites, distantly suppressing diet-induced atherosclerosis via regulation of intestinal homeostasis and inflammation.”

Atherosclerosis is a common chronic lipid-driven inflammatory cardiovascular disease with high morbidity and mortality. These findings provide a mechanistic explanation for adverse cardiovascular events in patients being treated for a range of inflammatory diseases.

This work was supported by Pew Scholar Award; a NCI P30 Cancer Center Grant; NCI R21 CA202396, NIH R56 HL133669, and NIH R01 HL133669; and NIH R01HL103866 This project was supported in whole or in part from Federal funds from the Frederick National Laboratory for Cancer Research, NIH under contract HHSN 261200800001E.

       

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