# Actin regulatory proteins regulate alveolar macrophage pro-inflammatory signaling

> **NIH NIH R56** · WASHINGTON UNIVERSITY · 2020 · $401,275

## Abstract

PROJECT SUMMARY
 Alveolar macrophages (AMs) are lung-resident phagocytes essential to pulmonary host defense.
Perturbation of AM biology contributes to a variety of lung diseases (including acute respiratory distress
syndrome and ventilator-induced lung injury) and to susceptibility to respiratory infections. Detailing the
molecular mechanisms that control AM activation and development will therefore inform new therapeutic
strategies to modulate pulmonary inflammation in multiple diseases. During the course of our initial award, we
discovered that mice lacking the actin-bundling protein L-plastin (LPL; LPL-/- mice) were profoundly susceptible
to pneumococcal lung infection. We discovered that susceptibility to lung infection correlated with a deficit of
AMs, and we confirmed an AM-specific requirement for LPL in bacterial clearance using CD11c.Cre-specific
deletion of LPL (newly generated CD11.Cre+-LPLfl/fl mice). We then leveraged our expertise and reagents to
probe a novel and significant finding that AM development specifically requires LPL (Blood, 2016).
 This renewal is built upon published and preliminary data generated while investigating the role of LPL in
AM development and function. First, we found that LPL is specifically required for the migration of AM precursor
cells (monocytes and/or pre-AMs) into the alveolar space, where the essential growth factor GM-CSF is
produced. Second, we found that LPL enables the migration of monocytes and macrophages by supporting
podosomes. Podosomes are integrin-mediated, F-actin-based organelles that promote macrophage adhesion
and migration. Podosomes also mediate mechanotransduction, translating mechanical force exerted upon the
cell into intracellular signaling that alters macrophage biology. Third, we found that AMs from LPL-/- mice
exhibited defective IL-1β production after NLRP3 inflammasome activation, and that NLRP3 inflammasome
activation was mechanosensitive. Finally, we found that airway administration of exogenous GM-CSF to neonatal
LPL-/- mice, during the normal temporal window of AM development, rescued AM numbers and protected adult
animals from subsequent bacterial infection. From these findings, we formulated our central hypothesis: LPL,
via its function in podosomes, mediates mechanotransduction that regulates macrophage pro-inflammatory
signaling. We will test this hypothesis by 1) defining, in unprecedented detail, the formation of podosomes in the
presence and absence of LPL; 2) determining which macrophage pro- and anti-inflammatory states require LPL
and/or are mechanosensitive; and 3) defining mechanisms by which GM-CSF regulates AM mechanosensitivity
and IL-1β production in WT and LPL-deficient AMs to show that AM biology can be therapeutically modified. The
combination of the PI's experience in cell biology, immunology and infectious disease, the assembled team of
collaborators, and the environment at Washington University ensure that this work will be accomplished.
Completi...

## Key facts

- **NIH application ID:** 10065309
- **Project number:** 2R56AI104732-06A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Sharon Celeste Morley
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $401,275
- **Award type:** 2
- **Project period:** 2014-04-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065309

## Citation

> US National Institutes of Health, RePORTER application 10065309, Actin regulatory proteins regulate alveolar macrophage pro-inflammatory signaling (2R56AI104732-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10065309. Licensed CC0.

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