# Macrophage Modulation of Lung Fibrosis

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $707,569

## Abstract

Pulmonary fibrosis has emerged as the leading cause of death in patients with systemic sclerosis
(SSc)/scleroderma, yet currently available therapies are only marginally effective. While recent work from
several groups of investigators suggests a key role for lung macrophages in the development of pulmonary
fibrosis in patients with SSc, this remains an area of controversy as the specific population(s) of lung
macrophages that drive fibrosis and the molecular mechanisms by which they do so remain largely
unknown. In advance of this proposal, we have developed novel tools to elucidate macrophage heterogeneity
in the mouse and human lung including lineage tagging, flow cytometry and transcriptional profiling in order to
examine the differential role of tissue-resident alveolar macrophages, as compared to the monocyte-derived
alveolar macrophages recruited to the lung, in the pathogenesis of fibrosis. Using unbiased transcriptional
analysis (RNAseq) of flow-sorted macrophage populations over the course of the development of experimental
fibrosis, we identified genetic signatures of monocyte to alveolar macrophage differentiation and fibrosis.
Moreover, we have developed a murine model, which lacks the pathogenic monocyte-derived macrophage and
is thus unable to develop lung fibrosis. Specifically, mice with macrophage-specific deletion of caspase-8, a
cysteine-aspartic acid protease originally identified as a key initiator of the apoptotic death receptor pathway
and suppressor of necroptosis (CreLysMCasp8fl/fl or CreCD11cCasp8fl/fl), showed significantly attenuated fibrosis
and an inability for recruited monocytes to differentiate into pro-fibrotic monocyte-derived Siglec Flow
macrophages following intratracheal treatment with either bleomycin or an adenovirus encoding an active form
of TGF-β as compared to Casp8fl/fl, CreLysM or CreCD11c mice. Thus, this model is an ideal to tool to understand
the differentiation of monocytes into pro-fibrotic alveolar macrophages in response to lung injury. These model
systems will allow us to apply the transcriptional data to the study of monocytes from patients with SSc
differentiated into alveolar macrophages in the lungs of humanized mice and alveolar macrophages obtained
from patients with SSc at the time of lung transplantation. Our studies will test the hypothesis that
monocyte differentiation into pro-fibrotic Siglec Flow alveolar macrophages is essential for the
development of lung fibrosis in both mice and humans in three interrelated specific aims.

## Key facts

- **NIH application ID:** 9868318
- **Project number:** 5R01HL134375-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Harris R Perlman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $707,569
- **Award type:** 5
- **Project period:** 2017-02-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868318

## Citation

> US National Institutes of Health, RePORTER application 9868318, Macrophage Modulation of Lung Fibrosis (5R01HL134375-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9868318. Licensed CC0.

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