# Regulation of Neonatal Lung Inflammation by Novel Innate Immune Mechanisms

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $600,761

## Abstract

Abstract
Prematurity-related chronic respiratory disease, including bronchopulmonary dysplasia (BPD), is associated with
high morbidity, healthcare use, and expenditures. Inflammation in early life increases the risk of BPD develop-
ment, but the innate immune mechanisms behind this are poorly understood. Inflammatory stress induces the
expression of ligands for the activating receptor natural-killer group 2, member D (NKG2D), in diverse target cell
populations. NKG2D is a C-type lectin-like receptor, expressed by γδ T cells, NK cells, and other lymphocytes
that are enriched in fetal lungs. Ligand engagement and activation of NKG2D+ lymphocytes enhance inflamma-
tion and induce cytotoxicity. The goal of this proposal is to determine the mechanisms by which pulmonary
inflammation in early life induces NKG2D ligand expression on target cells and activates NKG2D+ lung lympho-
cytes (γδ T cells and NK cells), and how this in turn leads to BPD-like lung immunopathology. The hypothesis is
that early-life exposure to bacterial lipopolysaccharide (LPS) or hyperoxia up-regulates the expression of NKG2D
ligands (NKG2DLs) that engage and activate lung NKG2D+ lymphocytes leading to pulmonary inflammation,
cytotoxicity, and that in turn impairs alveolar and vascular development. Studies have implicated activated lym-
phocytes and γδ T cells, as well as IL-17A and other pro-inflammatory cytokines, as key drivers of inflammation
in preterm infants. Cytotoxic Granzyme B (GzmB)+ NKG2D+ cells and CD68+ macrophages that express the
human NKG2D ligands MHC class-I-related protein A (MICA) and MICB were found using tracheal aspirates of
premature infants who are mechanically ventilated in the first week of life and later develop BPD. Also, aspirate
MICA mRNA levels positively correlate with median FiO2. To investigate the contribution of lung lymphocytes
and NKG2DL-NKG2D signaling to lung inflammation, this team used a mouse model of BPD with chronic early-
life exposure to LPS. LPS increased IL-17a and GzmB expression in lung NKG2D+ γδ T cells and, to a lesser
extent, in NK cells. NKG2D blockade attenuated the effects of LPS on NKG2D+ γδ T cells, pro-inflammatory
cytokine and cytotoxic responses, and preserved alveolar growth. LPS also induced cellular stress pathways
and increased the expression of NKG2DLs (retinoic acid early transcript 1 (Rae-1) and murine UL16-binding
protein-like transcript 1 (MULT1)) in lung macrophages and epithelial cells. Rae-1 blockade attenuated LPS-
induced lung immunopathology. In a second BPD model, neonatal hyperoxia induced similar responses. These
findings point to a role for activated NKG2D+ lung lymphocytes and NKG2DLs as key inflammatory mediators in
BPD pathogenesis. The aims of this proposal are: 1. Map the cell fate and define the role of NKG2D+ lympho-
cytes (γδ T cells and NK cells) in early-life LPS- and hyperoxia-induced lung immunopathology. 2. Determine
the cellular sources for NKG2DLs and define the immunogenicity and r...

## Key facts

- **NIH application ID:** 10977129
- **Project number:** 1R01HL167716-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Antonia Petrova Popova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $600,761
- **Award type:** 1
- **Project period:** 2024-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10977129

## Citation

> US National Institutes of Health, RePORTER application 10977129, Regulation of Neonatal Lung Inflammation by Novel Innate Immune Mechanisms (1R01HL167716-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10977129. Licensed CC0.

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