# Neutrophil Extracellular Traps and Host Immunity

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $405,000

## Abstract

Project Summary
In addition to the classical mode of phagocytosis and intracellular oxidative killing of pathogens, a recently
discovered antimicrobial function of neutrophils is the formation of extracellular traps (Neutrophil Extracellular
Traps, NETs), which can trap and kill pathogens extracellularly. As NET formation (NETosis) generally requires
reactive oxygen species (ROS) generation, we and others have found that neutrophils from Chronic
Granulomatous Diseases (CGD) patients and Gp91phox-/- CGD mice with mutations in NADPH oxidase complex
exhibit impaired NET generation in-vitro and in-vivo in response to various stimuli and pulmonary bacterial
infection. We recently reported that Tamoxifen (TMX), an FDA approved selective estrogen receptor (ER)
modifier for treatment of breast cancer, induces antimicrobial NETs in CGD neutrophils in a ROS independent
manner. We further showed that activation of autophagy is necessary and sufficient to induce TMX-mediated
NETs. In addition to this seminal report, the premise of the proposed research is derived from our preliminary
data indicating a novel pathway of ROS-and ER-independent NETosis by TMX via a non-canonical autophagy
activation. The two proposed specific aims will establish TMX as NET-inducing agent with antimicrobial and anti-
inflammatory effect in preclinical murine CGD and human CGD neutrophils (Aim 1); and elucidate TMX-mediated
non-canonical autophagy signaling pathway in neutrophils that culminates in disintegration of nuclear lamina to
facilitate the release of NETs (Aim 2). Our studies provide important mechanistic insights into a novel autophagy
pathway activated by TMX which will have implications not only for NET research but also for exploiting
autophagy and NETs to treat infectious and autoimmune diseases. By leveraging neutrophils from a well-
characterized cohort of CGD patients at NIH Clinical Center, these studies also present an exciting opportunity
for preclinical testing of TMX in CGD to restore antimicrobial function of neutrophils to combat pneumonic
bacterial infections, frequently observed in these patients.

## Key facts

- **NIH application ID:** 10364737
- **Project number:** 5R01AI155582-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Jyotika Sharma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2021-03-04 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364737

## Citation

> US National Institutes of Health, RePORTER application 10364737, Neutrophil Extracellular Traps and Host Immunity (5R01AI155582-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10364737. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*