# Temporal regulation of pulmonary inflammation by MyD88 alternative pre-mRNA splicing

> **NIH NIH R01** · NATIONAL JEWISH HEALTH · 2022 · $563,723

## Abstract

ABSTRACT
Acute inflammatory diseases of the lungs affect more than 100 million people in the U.S. annually. The acute
inflammatory response in these patients is required to combat infection but also causes significant tissue
damage. Thus, proper resolution of inflammation is critical for patient recovery. Lung airspace macrophages
(AMs) serve as key orchestrators of the inflammatory response, functioning in both the initiation and resolution
of inflammation. However, the mechanisms used by AMs to direct the resolution of inflammation are
incompletely understood. Moreover, two different AM subsets modulate inflammation. Resident AMs are
present in the airspaces throughout life; they serve as first responders to pathogens but their inflammatory
programs are quickly down-regulated. Recruited AMs arise from circulating monocytes that migrate to the lung
during inflammation; inflammatory mediator production by these cells is more persistent than that of resident
AMs. The mechanisms that drive the divergent effects of these AM populations on inflammation remain to be
elucidates. We have found that alternative pre-mRNA splicing of MyD88, a signaling adaptor that functions in
multiple Toll-like receptor and IL-1 receptor signaling pathways, plays a key role in terminating pro-
inflammatory mediator production in AMs. Thus we hypothesize that altered splicing of MyD88 provides a
central brake on AM pro-inflammatory responses and serves to limit persistent inflammation. We further
postulate that the role of MyD88 alternative splicing differs in different AM subpopulations. To test this
hypothesis, we will investigate the physiological effect of alternative MyD88 splicing in: (1) mouse resident AMs
ex vivo and in vivo, (2) mouse recruited AMs ex vivo and in vivo, and (3) human AMs isolated from patients
with acute inflammatory lung disease. These studies will demonstrate the potential utility of targeting this
regulatory mechanism to treat patients with acute inflammatory lung disease.

## Key facts

- **NIH application ID:** 10413131
- **Project number:** 5R01HL148335-04
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** Scott Alper
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $563,723
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10413131

## Citation

> US National Institutes of Health, RePORTER application 10413131, Temporal regulation of pulmonary inflammation by MyD88 alternative pre-mRNA splicing (5R01HL148335-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10413131. Licensed CC0.

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