# SPLUNC1 and Neutrophilic Inflammation in Cystic Fibrosis

> **NIH NIH K01** · YALE UNIVERSITY · 2021 · $69,930

## Abstract

The original premise of our K01 proposal was that airway host-defense protein Short Palate Lung Nasal
epithelium Clone-1 (PLUNC, SPLUNC1) regulates inflammation and therefore could contribute to acute lung
injury (ALI) and tissue damage in CF and respiratory infections. We defined a novel immunomodulatory effect of
SPLUNC1 in enhancing LPS-induced IFNγ/IFNλ-associated inflammation that led us to refocus the last years of
the K01 award on an Influenza A virus (IAV) model of pneumonia, where IFN responses are critical. This led to
the submission of our R01 proposal "SPLUNC1-controlled mechanisms of ALI during influenza A infection".
 IAV mortality is largely due to respiratory failure, precipitated by lung inflammation and ALI. Therefore, a
better understanding of the mechanisms that drive lung inflammation and ALI caused by IAV is a critical unmet
need. IAV activates endosomal Toll-Like Receptors (TLR3/7/8/9) to induce Interferons (IFN) in airway and
immune cells, driving inflammation and causing ALI. The mechanisms underlying this process are not fully
understood and there are no specific therapies to prevent ALI or accelerate its resolution.
 We recently discovered that airway host defense protein PLUNC may increase lung inflammation and
ALI by enhancing IFNλ expression. IFNλ increases immune cell recruitment through IFN-stimulated genes, that
increase lung inflammation and ALI. PLUNC may modulate IFN by serving as a scaffold for nucleic acids and
immune signaling proteins, similar to other host defense peptides with TLR-binding motifs. PLUNC has dual
immunomodulatory properties and antiviral effects that decrease early epithelial inflammation but may
enhance lung inflammation and ALI later in the clinical course.
 In recent work we showed that Plunc-/- mice have impaired IFNλ induction that protects them from LPS-
induced lung inflammation and ALI. Our preliminary data now show that Plunc-/- mice are similarly protected
during IAV infection and that PLUNC may modulate this effect through interactions with TLR3. We will test the
hypothesis that PLUNC regulates lung inflammation through interactions with TLR3, and that blocking
PLUNC-controlled inflammation decreases ALI during IAV infection. We will define PLUNC-controlled ALI
mechanisms that can be modulated to decrease the morbidity and mortality of IAV. We will accomplish this
through these aims: Aim 1. Define the mechanisms by which PLUNC increases IFN responses and lung
inflammation during IAV infection; Aim 2. Define the therapeutic potential of inhibiting PLUNC to protect against
IAV-ALI and accelerate its recovery; and Aim 3. Define PLUNC-regulated immune response and single-cell
transcriptome profiles associated with ALI and its resolution in humans. Understanding the role of PLUNC-TLR3
interactions in ALI will provide therapeutic targets to limit IAV morbidity. The mechanisms proposed here offer
an opportunity for developments that would limit the impact of IAV on millions of individua...

## Key facts

- **NIH application ID:** 10393271
- **Project number:** 3K01HL125514-05S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Clemente Britto-Leon
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $69,930
- **Award type:** 3
- **Project period:** 2021-06-01 → 2022-01-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10393271

## Citation

> US National Institutes of Health, RePORTER application 10393271, SPLUNC1 and Neutrophilic Inflammation in Cystic Fibrosis (3K01HL125514-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10393271. Licensed CC0.

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