Atherosclerosis is a chronic inflammatory disease of the large arteries and a major cause of death among western populations. Various immune-mediated mechanisms are implicated in the initiation and progression of the disease. Cytokines are key mediators of inflammation and emerging players in the regulation of atherosclerosis. While neutralization of cytokines has been proven effective in auto-inflammatory diseases, the therapeutic benefit of targeting cytokines in atherosclerosis remains to be elucidated. IL23, a cytokine of IL6/IL12 superfamily, is produced by myeloid cells and regulates the production of IL17 and IL22 by T helper IL17 producing (Th17) cells and also by ?? T cells, and innate lymphoid cells of type 3 (ILC3) in various inflammatory models. As a result, IL23 deficiency leads to the reduction of IL17 and IL22 expression and, in most cases, attenuation of the inflammatory disease progression as it was demonstrated for inflammatory bowel disease (IBD), psoriasis, arthritis and cancer. Multiple reports demonstrated increased levels of IL23 in patients and animals with atherosclerosis, pointing out to possible pro-inflammatory pro-atherogenic role of IL23. Additionally, several studies have implicated IL17A, a key cytokine regulated by IL23, as important pro-atherogenic mediator. These findings led us to speculate that IL23 would promote atherosclerosis, likely via upregulation of IL17 production by CD4 Th17 cells. Our preliminary data, however, revealed an unexpected atheroprotective role for IL23 in genetic mouse model of atherosclerosis. Here we propose to investigate the mechanism(s) by which IL23 suppresses atherosclerosis development. Based on our preliminary findings, we hypothesize that IL23-IL23R signaling regulates the inflammatory mileu in atherosclerosis by at least two mechanisms: (1) by directly suppressing expression of the pro-inflammatory molecule osteopontin (OPN) from myeloid cells in the aortas, and (2) indirectly, by controlling IL22 in the intestine and limiting the dysbiotic outgrowth of pro-inflammatory bacterial species of the gut microbiota. To study molecular and cellular mechanisms of atheroprotective action of IL23, we will use a well-established model of atherosclerosis (Ldlr-/- mice) coupled with conditional inactivation of IL23R (IL23R ?floxed? mice) and its potential downstream targets OPN and IL22 (OPN knockout mice and IL22R conditional mice). We will also use cutting edge molecular biology and histological techniques, as well as perform comprehensive analysis of intestinal microbiota as a potential driver of atherosclerosis in the absence of protective IL23 signaling. Overall, the proposed research will uncover the role of IL23 signaling in atherosclerosis. This work has strong translational potential because it will shed light on unexplained major adverse cardiovascular events (MACE) seeing in clinical trials with IL23 inhibitors.

Public Health Relevance

Cardiovascular diseases including atherosclerosis represent a growing healthcare burden in developed countries. We have discovered a new role of the cytokine IL23 in atherosclerosis development, allowing us to put forward the exciting proposition that IL23 actually may play an immunoregulatory role in conditions of hypercholesterolemia and thus protect from atherosclerosis. Therefore the systemic blockade of IL23 by immunotherapeutic approaches may actually trigger cardiovascular system complications, and need to be regarded with great caution; in this proposal, we will define the mechanism(s) by which IL23 mediates its atheroprotective effect.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56HL133669-01
Application #
9324427
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Olive, Michelle
Project Start
2016-09-06
Project End
2017-08-31
Budget Start
2016-09-06
Budget End
2017-08-31
Support Year
1
Fiscal Year
2016
Total Cost
$446,250
Indirect Cost
$196,250
Name
Research Institute of Fox Chase Cancer Center
Department
Type
DUNS #
064367329
City
Philadelphia
State
PA
Country
United States
Zip Code
19111