# Neutrophil A2A receptors in sepsis

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $536,296

## Abstract

SUMMARY
Sepsis is a clinical syndrome that complicates severe infection. Sepsis remains the leading cause of morbidity
and mortality in critically ill patients. There are no specific FDA-approved medicines for the treatment of sepsis.
Current concepts of the pathophysiology of sepsis suggest that inappropriate regulation of neutrophil functions
contribute to organ failure and mortality in sepsis. This manifests as an inability to control bacterial growth and
dissemination, persistent and secondary infections, inflammation, and end organ injury. Extracellular adenosine
is a biologically active signaling molecule that accumulates at sites of metabolic stress in sepsis. Extracellular
adenosine has potent immunosuppressive effects by binding to and activating G protein-coupled A2A adenosine
receptors (ARs) on the surface of neutrophils. A2AAR signaling reproduces many of the phenotypic changes in
neutrophils that are characteristic of sepsis, including decreased chemotaxis, diminished ability to ingest and kill
bacteria and delayed apoptosis. Given this similarity between septic neutrophil alterations and the ones caused
by A2AAR signaling, we hypothesized that endogenous adenosine would contribute to the sepsis-induced onset
of neutrophil dysfunction via stimulation of A2AARs. Our preliminary data using both targeted genetic deletion
and pharmacological antagonism in mice with cecal ligation and puncture-induced sepsis have confirmed that
A2AARs contribute to bacterial dissemination, organ injury, and mortality. Our data with human patients
demonstrate increased plasma adenosine and neutrophil A2AAR expression indicating increased A2AAR
signaling leading to neutrophil dysfunction. Based on these data, we hypothesize that endogenous adenosine
contributes to sepsis-induced immune dysregulation, bacterial dissemination, organ injury and mortality through
A2AAR signaling in neutrophils. To address this hypothesis, we propose 2 Specific Aims. Specific Aim 1 will
delineate the role of A2AAR signaling in neutrophils in contributing to bacterial dissemination, organ injury, and
mortality in CLP-induced sepsis in mice. Specific Aim 2 will study the contribution of A2AAR signaling to neutrophil
dysfunction in patients with sepsis. The long-term goal of this study is to pharmacologically target A2AAR signaling
as a treatment option for the management of patients with sepsis.

## Key facts

- **NIH application ID:** 10478933
- **Project number:** 5R01HL158519-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** George HASKO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $536,296
- **Award type:** 5
- **Project period:** 2021-09-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10478933

## Citation

> US National Institutes of Health, RePORTER application 10478933, Neutrophil A2A receptors in sepsis (5R01HL158519-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10478933. Licensed CC0.

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