# Pathogenic Wnt-beta catenin target genes in macrophages and fibrosis

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $651,098

## Abstract

Systemic sclerosis (SSc)/scleroderma, is the prototypic fibrotic disease causing skin and internal organ
fibrosis. Lung fibrosis progression as a patient ages is the leading cause of SSc-related deaths. It is likely that
a common effector cell drives fibrosis in multiple organs in SSc, and our preliminary data demonstrate that
circulating monocytes are recruited to injured tissues where they differentiate into “monocyte-derived”
macrophages. Using a murine model of lung fibrosis, we performed causal genetic experiments and showed
that these monocyte-derived tissue macrophages are critical for the fibrosis development. Unbiased
transcriptional profiling of flow-sorted monocyte-derived alveolar macrophages in mice during lung fibrosis, and
in human alveolar macrophages from lung explants from patients with SSc undergoing transplantation, showed
altered signaling through the Wnt/β-catenin pathway. We found that genetic loss-of- function in Wnt/β-catenin
signaling in murine lung macrophages did not affect fibrosis severity, but sped the resolution of fibrosis. These
findings are reminiscent of those in aged animals in which fibrosis persists much longer after bleomycin
administration compared with young mice. Indeed, the persistence of fibrosis after injury is a characteristic
feature of human fibrosis in multiple organs. Furthermore, we found age-related changes in Wnt/β-catenin
pathway components in transcriptomes generated from flow sorted alveolar macrophages collected over the
lifespan of mice (4-24 months). These findings support our hypothesis that a gain of function in Wnt/β-catenin
signaling in monocyte-derived macrophages contributes to the age-related susceptibility to persistent fibrosis in
multiple organs. We propose to test this hypothesis in two interrelated specific aims. In Aim 1, we will
determine whether genetic gain- or loss-of-function of Wnt/β-catenin signaling in monocyte-derived
macrophages cells enhances or prevents the differential susceptibility of aged animals to multiple organ
fibrosis. In Aim 2, we will determine whether a common deregulated Wnt pathway-related gene expression
signature is present in tissue macrophages isolated from the lung and skin of patients with SSc compared to
healthy control subjects. Our previous work using whole skin biopsies from mice and SSc patients,
demonstrated that alterations in the Wnt/β-catenin system are involved with SSc dermal fibrosis. We now
propose to capitalize upon our combined expertise in macrophage biology and Wnt/β-catenin signaling to
determine their contribution to accelerated SSc dermal and lung fibrosis in the aged. Altogether, this proposal
matches a proven investigative team with a compelling hypothesis that stands to transform the way we think
about aging-related fibrosis.

## Key facts

- **NIH application ID:** 10216175
- **Project number:** 5R01AR073270-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** MONIQUE Evangeline HINCHCLIFF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $651,098
- **Award type:** 5
- **Project period:** 2019-07-03 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216175

## Citation

> US National Institutes of Health, RePORTER application 10216175, Pathogenic Wnt-beta catenin target genes in macrophages and fibrosis (5R01AR073270-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10216175. Licensed CC0.

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