# The unexpected role of IL-23 cytokine in atherosclerosis

> **NIH NIH R01** · RESEARCH INST OF FOX CHASE CAN CTR · 2020 · $67,891

## Abstract

Project Summary/Abstract
 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 into 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 γδ T cells, and type 3 innate lymphoid cells (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 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.

## Key facts

- **NIH application ID:** 9932481
- **Project number:** 5R01HL133669-04
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** Ekaterina Koltsova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,891
- **Award type:** 5
- **Project period:** 2017-09-01 → 2020-09-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932481

## Citation

> US National Institutes of Health, RePORTER application 9932481, The unexpected role of IL-23 cytokine in atherosclerosis (5R01HL133669-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9932481. Licensed CC0.

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