# Wnt-beta-catenin cross interactions in alveolar macrophages and epithelial cells in persistence of SSc-ILD

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $734,694

## Abstract

Project summary
Systemic sclerosis (SSc) is a progressive fibrotic disease for which there is no effective treatment.
Presently, the major cause of morbidity and mortality for patients with SSc is respiratory failure due to
pulmonary fibrosis. Despite how commonly interstitial lung disease (ILD) occurs in SSc, it remains poorly
understood and represents a major unmet medical need. The Wnt/-catenin (-cat) signaling pathway is
known to be crucial for cell fate decisions throughout development and adult tissue repair after injury. Work
from our group and others have shown that the Wnt/β-cat pathway is aberrantly activated in systemic
sclerosis and the associated ILD. Subsequent studies from our laboratory provided the first evidence that
global genetic loss of the Wnt co-receptor Lrp5, resulting in reduced β-cat signaling, was protective against
bleomycin-induced pulmonary fibrosis and that, in the peripheral blood mononuclear cells from two
independent cohorts of Idiopathic Pulmonary Fibrosis (IPF) subjects, Wnt signaling as one of the top 2 over-
represented pathways associated with worsened prognosis. We have generated extensive preliminary data
demonstrating that sustained β-cat signaling in lung macrophages promotes the persistence of lung fibrosis
after both bleomycin- and asbestos-induced injuries in mice, suggesting that macrophages are a key cell
type through which -cat signaling drives fibrosis. Our preliminary data also reveal that the alveolar
macrophage population is increased in SSc-ILD lungs, where lung transcriptomes from SSc-ILD and IPF
subjects share common genes. Thus, based on these findings, we reason that the signals that drive
macrophage recruitment, differentiation and perdurance after tissue injury are conserved across fibrotic
diseases through a common Wnt/-cat regulatory axis. We hypothesize that Wnt/-cat signaling is required
for the differentiation of monocytes into recruited alveolar macrophages and that injured lung alveolar
epithelium provides a contextual Wnt signal that maintains a pro-fibrotic milieu for these recruited
macrophages, thus aggravating lung repair and promoting the persistence of fibrosis. We propose 1) to
determine the role Wnt/β-cat signaling to the differentiation of monocytes-macrophages in the persistence of
fibrosis in SSc-ILD, 2) to determine the contribution of Wnt signaling from the injured alveolar epithelium in
maintaining the pro-fibrotic macrophage phenotype in SSc-ILD, and 3) to determine the monocyte-
macrophage subpopulations from subjects with SSc-ILD that express enrichment for Wnt pathway genes.
We will use human blood and lung samples from subjects with SSc-ILD and complementary in vivo
approaches using competitive and shielded chimeric mice, macrophage-specific transgenic mice targeting
β-cat and Wnt ligands, and chemical ablation to dissect the relative contributions of Wnt/β-cat signaling in
macrophages and epithelial cells necessary for repair after lung injury and in SSc-...

## Key facts

- **NIH application ID:** 10063540
- **Project number:** 5R01HL134800-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Cara J Gottardi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $734,694
- **Award type:** 5
- **Project period:** 2017-12-22 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10063540

## Citation

> US National Institutes of Health, RePORTER application 10063540, Wnt-beta-catenin cross interactions in alveolar macrophages and epithelial cells in persistence of SSc-ILD (5R01HL134800-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10063540. Licensed CC0.

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