# Mechanisms of lung macrophage programming by MUC5B during health and disease

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $634,941

## Abstract

PROJECT SUMMARY
Mucus and macrophages protect the lungs in health, but they can also contribute to disease following lung
injury. How their protective vs. pathological functions are calibrated is poorly understood. We seek to
determine mechanisms that control their interactions during responses to lung injury. For mucus-mediated
defense, the mucin glycoprotein MUC5B is essential. In mice, absence of Muc5b causes particles and
bacteria to accumulate in the lungs, ultimately resulting in early mortality. Despite its requirement for health,
MUC5B is an important risk factor in human pulmonary fibrosis, where it is misexpressed in bronchiolar club
cells and type 2 alveolar epithelia. Overexpression of Muc5b in these cell types in mice potentiates fibrosis
following bleomycin-induced lung injury. These data suggest that the levels and locations of MUC5B/Muc5b-
expression are significant factors in the pathogenesis of pulmonary fibrosis. Nonetheless, we do not yet fully
understand cellular and molecular mechanisms that explain how MUC5B/Muc5b promotes lung fibrosis. Our
recent work suggests that defensive and pathologic effects of airway mucus are regulated by interactions
between Muc5b and airspace macrophages (AMs). Resident AMs are present constitutively and are required
for non-inflammatory defense. In response to injury, AM pools increase through recruitment of blood
monocytes that mature into macrophages. These recruited AMs are more inflammatory than resident AMs, but
they are also short-lived, resulting in transient expansion and then contraction of the AM pools. Mechanisms of
acute and resolving inflammation that distinguish resident and recruited AM types also impinge on fibrotic
repair. The presence of both MUC5B/Muc5b and AMs in distal airspaces, along with our prior observation of
AM dysfunction in Muc5b knockout mice, implicate a connection between MUC5B/Muc5b and AM functions.
We identified a potential mechanism mediated by mucin glycans and AM glycan receptors. MUC5B/Muc5b is
heavily coated with sialic acid (SA) that is attached to galactose via an α2,3-linkage. It is also a ligand for sialic
acid binding immunoglobulin like lectin-F (Siglec-F), an inhibitory signaling molecule found almost exclusively
on AMs in healthy lungs. We found that a Muc5b-SA-Siglec-F axis is critical for resolving inflammation, as
shown by prolonged recruited AM accumulation in mice lacking each component. We now also show that
bleomycin-induced lung fibrosis is suppressed in Muc5b-SA-Siglec-F axis disrupted mice. Thus, while
protective in response to bacterial inflammation, this mechanism appears to be detrimental in a pro-fibrotic
injury setting. We hypothesize that fibrotic repair of lung tissues is mediated by a Muc5b-SA-Siglec-F
dependent AM programming mechanism. This will be tested in three aims that test whether 1) promotion of
lung fibrosis by Muc5b requires α2,3-sialylation; 2) ligation of Siglec-F by sialylated Muc5b mediates fibrosis;
and 3) the Mu...

## Key facts

- **NIH application ID:** 10829799
- **Project number:** 5R01HL130938-07
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Christopher M Evans
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $634,941
- **Award type:** 5
- **Project period:** 2016-08-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10829799

## Citation

> US National Institutes of Health, RePORTER application 10829799, Mechanisms of lung macrophage programming by MUC5B during health and disease (5R01HL130938-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10829799. Licensed CC0.

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