# Extracellular vesicle-driven neutrophilic inflammation in cystic fibrosis lungs

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $732,831

## Abstract

PROJECT SUMMARY / ABSTRACT
Neutrophils are the most abundant leukocyte subset in humans. Current therapies targeting neutrophils are
limited to drugs that block their recruitment to tissues, leaving their functions mostly untouched. Our long-term
goal is to develop new knowledge on neutrophil biology and function in humans and derive from it innovative
treatments for conditions dominated by intractable neutrophil-driven inflammation, including cystic fibrosis (CF).
CF is the most frequent autosomal disease in people of European descent, caused by mutations in the CFTR
epithelial channel. Recent research has shown that CFTR dysfunction causes local mucus stasis obstruction,
followed by neutrophil recruitment, and paradoxically, opportunistic infections. This paradox stems from the
fact that most neutrophils recruited to CF airways in vivo undergo hyperactive granule release, and become
immunomodulatory and metabolically licensed, yet fail to kill microbes, in a functional fate we dubbed “GRIM”.
Using an organotypic model of human airway inflammation, we showed previously that naïve blood neutrophils
can be made to acquire the GRIM fate upon transepithelial migration in vitro into airway fluid from CF patients.
Further preliminary studies of GRIM adaptation presented here support an obligate upstream role for
extracellular vesicles (EVs) present in airway fluid carrying the long non-coding RNA MALAT-1, and the
downstream implication of transcriptional firing and mitochondrial rewrting, with histone deacetylase 11
(HDAC11) and cMyc as key modulators. Remarkably, we show that GRIM neutrophils produced in vitro
secrete secondary EVs that can in turn induce GRIM adaptation in a new wave of neutrophils. Also, we show
that siRNA against MALAT-1 and HDAC11 and inhibition of HDAC11 by the small molecule drug SIS17
normalize granule release and bacterial killing by GRIM neutrophils, as well as their release of secondary EVs.
Our objective is to fully characterize mechanisms of GRIM adaptation in CF airway neutrophils. Our central
hypothesis is that chronic CF airway inflammation is a feed-forward process in which resident GRIM
neutrophils release EVs that induce the GRIM fate in newly recruited neutrophils.
This study introduces a new and innovative basic paradigm of neutrophil-driven human lung inflammation with
key roles for EVs, MALAT-1, HDAC11 and cMyc, and innovative methods to deconstruct this paradigm (model
for mass production of lung-recruited neutrophils, optimized tools to characterize lung EVs, and drug- / RNA /
siRNA interventions targeted at neutrophils). We expect this study to yield transformative findings in our basic
understanding and ability to treat chronic neutrophilic inflammation and infection in CF and other diseases.

## Key facts

- **NIH application ID:** 10875571
- **Project number:** 5R01HL159058-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Rabindra Marie-Jean Tirouvanziam
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $732,831
- **Award type:** 5
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10875571

## Citation

> US National Institutes of Health, RePORTER application 10875571, Extracellular vesicle-driven neutrophilic inflammation in cystic fibrosis lungs (5R01HL159058-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10875571. Licensed CC0.

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