# Very early drivers of neutrophilic inflammation in cardiac ischemia-reperfusion

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $704,821

## Abstract

PROJECT SUMMARY/ABSTRACT
 Neutrophils are a key drivers of immune mediated reperfusion injury in the heart after ischemia-reperfusion
(MI/R). They rapidly infiltrate the heart within minutes, directly cause damage through effector functions, and
dictate subsequent inflammatory events through environmental alterations, cytokine release, and interactions
with other immune cells. We performed single cell RNA sequencing on cardiac-infiltrating neutrophils to
uncover the diversity in neutrophil populations as well as novel pathways. We identified neutrophils with a type
I interferon (IFN-I) signature, a pathway traditionally associated with host viral defense. The role of IFN-I in
cardiac neutrophils is unknown. In preliminary experiments, we document that inhibiting the IFN-I pathway
during the peak of neutrophil activation in the first 24 hours after MI/R improves cardiac recovery. We also
found that cardiac infiltrating neutrophils express IFN-I and have upregulated interferon sensitive genes (ISGs)
suggesting they may both produce and respond to IFN-I.
 In order to precisely study this pathway, we have made two unique mice strains lacking the ‘stimulator of
interferon gene response’ (STING) or the type I interferon receptor (IFNAR1) only in neutrophils. STING is a
key activator of IFN-I transcription and IFNAR1 is the receptor for IFN-I. In this proposal we will first explore
the effects of IFN-I on neutrophil biology using human neutrophils in ex vivo assays, as well as mouse in vivo
studies. Next, we will subject neutrophil-specific STING knock out mice to MI/R and precisely characterize
changes to acute inflammatory events, sub-acute, and chronic inflammatory events, and cardiac recovery.
Inflammatory events such as immune cell phenotypes, local and systemic cytokines, and neutrophil function
will be precisely characterized. Lastly, we will explore the same endpoints in mice lacking the ability to detect
IFN-I due to neutrophil specific IFNAR1 knockout. The overarching hypothesis of this proposal is as follows:
Neutrophil initiation of and response to IFN-I are key early drivers of neutrophilic inflammation and set off
detrimental inflammatory cascades culminating in impaired cardiac function after MI/R.
 If correct, an IFN-I targeted therapy administered during neutrophilic inflammation early after MI/R may
improve recovery and be a clinically feasible intervention. An IFN-I antagonist has recently been approved as a
treatment for lupus and could be repurposed for this indication. Treatment for only 24 hours would be required
to fully cover the timeframe of neutrophilic inflammation but could greatly influence downstream inflammation
and optimize the heart for maximal recovery.

## Key facts

- **NIH application ID:** 10882111
- **Project number:** 2R01HL140223-06A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Rebecca Diane Levit
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $704,821
- **Award type:** 2
- **Project period:** 2018-08-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882111

## Citation

> US National Institutes of Health, RePORTER application 10882111, Very early drivers of neutrophilic inflammation in cardiac ischemia-reperfusion (2R01HL140223-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10882111. Licensed CC0.

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