# Role of ECM-associated IL-33 in Functional Remodeling After Myocardial Infarction

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $45,520

## Abstract

PROJECT SUMMARY/ABSTRACT
Ischemia during myocardial infarction (MI) causes sudden cardiomyocyte death that initiates an intense
inflammatory response, but timely resolution of the inflammatory phase is necessary to move into the reparative
phase and minimize scarring. A prolonged pro-inflammatory phase is associated with an adverse ventricular
remodeling response that can progress to clinical heart failure. Current therapeutic options are limited and fail to
prevent or reverse immune-driven fibrosis after myocardial infarction. The theme of the proposed work is that IL-
33 driven modulation of the immune response can minimize fibrosis and preserve myocardial function after
ischemic injury. Bioscaffolds composed of extracellular matrix (ECM) have been shown to minimize scarring
after MI in rodent models, but the underlying mechanisms are only partially understood. The identification of
interleukin-33 (IL-33) stably stored within the ECM suggests a potential role in the ECM-mediated
immunomodulation and constructive remodeling response. Emerging evidence shows that IL-33 supports tissue
repair, especially in models of cardiovascular disease, by signaling through its cognate receptor, ST2. IL-33 has
previously been considered a nuclear protein, but recent studies have found IL-33 stably integrated into the ECM
by encapsulation within matrix bound nanovesicles (MBV) that are released during ECM degradation to target
infiltrating immune cells. We have found that MBV containing IL-33 can direct macrophage differentiation toward
a pro-remodeling M2 phenotype through a pathway that does not involve the ST2 receptor. The identification of
an ST2-independent IL-33 signaling mechanism induced by MBV is novel in itself but is particularly important in
the context of myocardial infarction because expression levels of a soluble, antagonistic form of ST2 are
increased following MI injury and associated with poor prognosis. It is hypothesized that MBV within the ECM
are a critical source of IL-33 necessary to mediate early ST2-independent pro-remodeling macrophage
differentiation and direct constructive remodeling after myocardial ischemia. The proposed studies will first define
the repertoire of genes regulated by the ST2-independent signaling mechanism in macrophages and then
investigate the role of IL-33 mediated immunomodulation in preventing immune-driven fibrosis. The results of
this work my enable novel immunomodulatory approaches to protect the myocardium after ischemic injury.

## Key facts

- **NIH application ID:** 9910651
- **Project number:** 1F31HL151083-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Madeline Cramer
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9910651

## Citation

> US National Institutes of Health, RePORTER application 9910651, Role of ECM-associated IL-33 in Functional Remodeling After Myocardial Infarction (1F31HL151083-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9910651. Licensed CC0.

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