# Identification of a Damaging Subset of Neutrophils that Arises in Septic Patients

> **NIH NIH R01** · RHODE ISLAND HOSPITAL · 2021 · $504,012

## Abstract

ABSTRACT:
Sepsis is a “life-threatening organ dysfunction caused by a dysregulated host response to infection”.
Neutrophils become hyperactive during sepsis and they mediate much of the morbidity and mortality
associated with the disease. However the antimicrobial function of neutrophils provides benefit such that
depletion of the entire population of neutrophils in the septic patient would be immunosuppressive.
Heterogeneity of neutrophils has recently been described in disease states including cancer and lupus. Our
laboratories have discovered the presence of a small population of bloodstream neutrophils that overexpress
the integrin VLA3 (CD49c/CD29; a3b1) in ICU patients and experimental animals with sepsis. We have shown
that blockade or genetic depletion of neutrophil VLA3 has a survival advantage in septic mice. These findings
indicate that selective removal of the VLA3high subset improves outcome without impairment of innate host
defense against infection. In humans, neutrophils from septic patients demonstrate pronounced damage to the
barrier function of endothelial cells in vitro which is prevented by VLA3 blocking. This suggests that the primary
target of damage to the septic host by VLA3high cells is the vasculature. In addition, preliminary evidence also
shows that septic patients that have VLA3high neutrophils late into the disease have increased mortality as
compared to patients who do not show VLA3high cells in their blood. The overarching hypothesis to be
tested in this proposal is that a distinct, hyperinflammatory and damaging subset of blood neutrophils,
which express high levels of VLA3, arises in the circulation of ICU patients with sepsis. It is
hypothesized further that the presence of circulating VLA3high neutrophils predicts severity of the disease as
determined by clinical scoring, and that VLA3 represents a druggable target for attenuation of inflammatory
damage to the septic patient while avoiding overt immunosuppression. Three specific aims are put forth to test
these hypotheses. Aim 1 will determine the correlation between VLA3 expression and activation on peripheral
blood neutrophils and illness severity in septic ICU patients. Aim 2 will use human cells and multiphoton
imaging of septic mice to test the hypothesis that VLA3high neutrophils comprise a hyperinflammatory subset
that causes vascular damage and capillary leak. Aim 3 will characterize the VLA3high and VLA3low neutrophil
subsets and examine the mechanisms through which they impair endothelial barrier function. Taken together,
this proposal addresses mechanisms regarding how the dysregulated host response threatens patient survival
and offers a molecular target for dampening the destructive arms of the hyperinflammatory response while
preserving the beneficial aspects of immune defense.

## Key facts

- **NIH application ID:** 10179456
- **Project number:** 5R01HL147525-03
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** Minsoo Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $504,012
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179456

## Citation

> US National Institutes of Health, RePORTER application 10179456, Identification of a Damaging Subset of Neutrophils that Arises in Septic Patients (5R01HL147525-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10179456. Licensed CC0.

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