# Role of Sex in Immune Stromal cell Interactions driving cardiovascular lesions in Kawasaki Disease vasculitis

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2024 · $582,830

## Abstract

PROJECT ABSTRACT
Kawasaki disease (KD), an acute febrile illness and systemic vasculitis of unknown etiology, is the leading cause
of acquired heart disease among children in the US. Coronary artery aneurysms (CAA) develop in as many as
25% of untreated KD patients, resulting in ischemic heart disease, myocardial infarction, and even death.
Although intravenous IgG (IVIG) treatment within the first 10 days of illness significantly reduces the likelihood
of cardiovascular complications, up to 25% of KD patients are IVIG-resistant and at higher risk of developing
CAA. Therefore, a better understanding of the immune and pathological mechanisms leading to the development
of KD vasculitis is needed to identify more efficacious KD therapeutics and prevent the long-term cardiovascular
sequelae stemming from tissue inflammation and coronary remodeling. KD occurs more frequently in males, and
male patients experience more severe disease than female patients. However, the mechanisms underlying this
sex disparity are unknown. In both the human disease and a murine model of KD vasculitis, the NLRP3-IL-1β
axis has been identified as a key driver of pathogenesis. Our preliminary data indicate that vascular tissue-
infiltrating monocytes, macrophages and dendritic cells are the main cellular sources of IL-1β during murine KD.
We have also shown that vascular smooth muscle cells (VSMCs) surrounding the coronary artery undergo a
phenotype switch, acquiring properties of fibromyocytes and synthetic VSMCs. This phenotype switch may
contribute to luminal myofibroblast proliferation in the murine model of KD vasculitis. Importantly, we find
enhanced IL-1β production and signaling, increased inflammatory monocytes and neutrophils, and enhanced
VSMC phenotype switching in male KD mice compared with females. Based on our strong published and
preliminary evidence, our central hypothesis is that differences in IL-1β-mediated immune-stromal cell
interactions drive the sex disparity in KD. We will test this hypothesis in the following aims: Establish the
contribution of monocytes, macrophages, and neutrophils to disease pathogenesis in male and female mice
during LCWE-induced KD vasculitis (Aim 1); Establish the contribution of sex differences in vascular smooth
muscle cell function to sexual dimorphism in LCWE-induced vasculitis (Aim 2). The completion of these studies
will determine the fundamental mechanisms that mediate sex-based differences in cardiovascular lesion
development in KD, which may lead to novel therapeutic approaches.

## Key facts

- **NIH application ID:** 10990212
- **Project number:** 1R01HL170580-01A1
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Moshe Arditi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $582,830
- **Award type:** 1
- **Project period:** 2024-09-15 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10990212

## Citation

> US National Institutes of Health, RePORTER application 10990212, Role of Sex in Immune Stromal cell Interactions driving cardiovascular lesions in Kawasaki Disease vasculitis (1R01HL170580-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10990212. Licensed CC0.

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