# Neutrophils in Sepsis: Role of CIRP

> **NIH NIH R01** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2021 · $330,000

## Abstract

PROJECT DESCRIPTION: This R01 project's goal is to investigate the mechanism by which cold-inducible
RNA-binding protein (CIRP) increases sepsis severity and causes acute lung injury (ALI). Sepsis and ALI are
deadly and have no FDA-approved treatment. CIRP is a nuclear protein that can be released into the
circulation during sepsis, increasing sepsis severity and causing ALI. We have discovered that CIRP
increases a novel subset of neutrophils characterized by surface expression of intercellular adhesion molecule-
1 (ICAM-1). We found that ICAM-1+ neutrophils were expanded in the blood and lungs of septic mice, but not
in CIRP knockout mice. We further showed that stimulation with CIRP was sufficient to induce ICAM-1+
neutrophils. For the first time, we discovered that CIRP-induced ICAM-1+ neutrophils produced much higher
levels of neutrophil extracellular traps (NETs). Based on these novel findings, we hypothesize that CIRP
induces NET-forming ICAM-1+ neutrophils to cause ALI in sepsis. We also showed that C23, a peptide derived
from human CIRP, dose-dependently inhibits CIRP-induced release of TNF-α and inhibits CIRP induction of
ICAM-1+ neutrophils. Thus, we further hypothesize that C23 attenuates sepsis-induced ALI by reducing CIRP-
induced NET-forming neutrophils. We will first demonstrate CIRP's induction of NET-forming ICAM-1+
neutrophils and their deleterious effects, both in vitro and in vivo. Next, we will identify key signaling pathways
through which CIRP induces NET-forming ICAM-1+ neutrophils. Finally, we will examine C23's ability to
suppress NET-forming ICAM-1+ neutrophils, decrease sepsis and ALI severity, and increase sepsis survival.
These studies will improve our understanding of how CIRP induces NET-forming neutrophils to cause
inflammation and tissue injury and support the development of C23 as a new and effective treatment for
patients with sepsis and ALI.

## Key facts

- **NIH application ID:** 10197957
- **Project number:** 5R01GM129633-04
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Monowar Aziz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $330,000
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197957

## Citation

> US National Institutes of Health, RePORTER application 10197957, Neutrophils in Sepsis: Role of CIRP (5R01GM129633-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10197957. Licensed CC0.

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