# Chi3L1 regulates NET formation during bacterial pneumonia

> **NIH NIH F32** · YALE UNIVERSITY · 2020 · $60,281

## Abstract

PROJECT SUMMARY
Pneumonia is a common and deadly disease, claiming four million lives per year worldwide. Immune defense in
pneumonia primarily depends on neutrophils, which kill pathogens via phagocytosis or release of neutrophil
extracellular traps (NETs). NETs are weblike structures of chromatin complexed with microbicidal proteins that
help eliminate bacteria during pneumonia, but also damage host lung tissue. In the clinical setting, where
antibiotic use ensures bacterial clearance, NETs are largely pathologic. However, there are no therapies that
target NET formation. Chi3L1 is an evolutionarily ancient, but poorly understood lectin that binds to the chitin cell
walls of fungi, nematodes, and insects. Previous studies have shown that Chi3L1 promotes defense against
bacteria during lung infection through binding to the cytokine receptor IL13Rα2. Further work has shown that
Chi3L1-IL13Rα2 signaling activates AKT and ERK pathways in numerous cell types during lung injury to prevent
cell death. In neutrophils, AKT and ERK signaling similarly modulate cell death pathways, inhibiting apoptosis
and stimulating NETosis. Therefore, we speculated that Chi3L1 could contribute to bacterial clearance in
pneumonia by activating IL13Rα2, leading to downstream activation of AKT and ERK, inhibition of apoptosis,
and formation of bactericidal NETs. To test this prediction, we induced pneumonia in mice with Pseudomonas
aeruginosa, a nosocomial bacterial pathogen. In preliminary experiments, we showed that Chi3L1-deficient mice
have higher bacterial burdens, and that this was not explained by impaired neutrophil recruitment. Instead,
Chi3L1-deficient mice showed decreased NET formation. Furthermore, IL13Rα2-deficient mice demonstrated
the same decrease in NETs. Thus, as hypothesized, Chi3L1-IL13Rα2 signaling does regulate NETosis.
However, it remains unclear how P. aeruginosa, a bacterium surrounded by peptidoglycan (PG) – not a chitin
cell wall – could promote NETosis via the chitin-binding lectin Chi3L1. Structural similarities between PG and
chitin, along with the existence of protein families capable of recognizing both PG and chitin suggest a possible
answer: that Chi3L1 binds to PG as well. Thus, we hypothesize that Chi3L1 binds to bacterial cell walls during
pneumonia and promotes NETosis via IL13Rα2. To test this hypothesis, we propose the following two aims. 1)
Using well-characterized in vitro assays for NET formation, we will evaluate whether Chi3L1 directly activates
IL13Rα2 in isolated neutrophils. We will also test whether Chi3L1 stimulates NETosis via AKT and ERK, and
whether it inhibits apoptosis. 2) Next, we will use flow cytometry and microscopy to test if Chi3L1 is able to bind
peptidoglycan. Finally, using our in vitro assay for NET formation, we will test if Chi3L1 binding to its substrate
modulates its NETogenic effects. We believe these studies have potential to produce important insight into how
Chi3L1-IL13Rα2 signaling governs NET form...

## Key facts

- **NIH application ID:** 10068943
- **Project number:** 1F32HL154641-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** SAMIR GAUTAM
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $60,281
- **Award type:** 1
- **Project period:** 2020-09-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068943

## Citation

> US National Institutes of Health, RePORTER application 10068943, Chi3L1 regulates NET formation during bacterial pneumonia (1F32HL154641-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10068943. Licensed CC0.

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