Emergence of inflammatory fibroblasts with aging in Hermansky-Pudlak syndrome associated pulmonary fibrosis
The longitudinal cellular interactions that drive pulmonary fibrosis are not well understood. To investigate the disease underpinnings associated with fibrosis onset and progression, we generated a scRNA-seq atlas of lungs from young and aged mouse models of multiple subtypes of Hermansky-Pudlak syndrome (HPS), a collection of rare autosomal recessive diseases associated with albinism, platelet dysfunction, and pulmonary fibrosis. We have identified an age-dependent increase in SAA3<sup>+</sup> inflammatory lung fibroblasts in HPS mice, including in double-mutant HPS1-2 mice which develop spontaneous fibrosis. HPS1 fibroblasts show increased expression of IL-1R1, whereas alveolar type II epithelial cells from HPS2 mice induce the inflammatory gene signature in co-cultured fibroblasts. scRNA-seq of lung tissue from three HPS1 patients similarly shows the presence of inflammatory fibroblasts and increased IL1R1 expression on fibroblasts. These data posit complex interactions between dysfunctional epithelial cells, inflammatory fibroblasts, and recruited immune cells, suggesting potential opportunities for mitigation of the fibrotic cascade.
Authors
- Jonathan A. Kropski (ORCID: https://orcid.org/0000-0002-8923-1344)
- Lisa R. Young (ORCID: https://orcid.org/0000-0003-3297-8532)
- Jeremy Katzen (ORCID: https://orcid.org/0000-0001-9208-7729)
- Edward Cantu (ORCID: https://orcid.org/0000-0003-1105-0129)
- Jason J. Gokey (ORCID: https://orcid.org/0000-0001-8244-7831)
- Jarod A. Zepp (ORCID: https://orcid.org/0000-0002-2468-8087)
- Joanna Y. Wang (ORCID: https://orcid.org/0000-0002-0305-1810)
- Amir Emtiazjoo
- Sneha Sitaraman (ORCID: https://orcid.org/0000-0001-8541-9190)
- Jamie L. Todd (ORCID: https://orcid.org/0000-0003-4247-3693)
- Brandon J. H. Banaschewski
- David B. Frank (ORCID: https://orcid.org/0000-0002-3064-2069)
- Ruby Pan (ORCID: https://orcid.org/0000-0002-5202-5280)
- Maria C. Basil (ORCID: https://orcid.org/0000-0003-4716-1285)
- Mary Kate Goldy
- D. Stewart (ORCID: https://orcid.org/0009-0000-4155-1747)
- Susan M. Lin (ORCID: https://orcid.org/0000-0002-2415-8350)
- Nigel S. Michki (ORCID: https://orcid.org/0000-0003-0403-0648)
Institutions
- Children's Hospital of Philadelphia (US)
- Vanderbilt University (US)
- Hospital of the University of Pennsylvania (US)
- University of Florida (US)
- Clinical Research Institute (US)
- Lung Institute (US)
- Duke Medical Center (US)
- University of Pennsylvania (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-02-22
- DOI
- https://doi.org/10.1038/s42003-025-07589-9
- Citations
- 8
- Primary Topic
- Systemic Sclerosis and Related Diseases
- Type
- article
- Field-Weighted Citation Impact
- 11.77
Funders
- Hermansky-Pudlak Syndrome Network
- Children's Hospital of Philadelphia
- National Institutes of Health
- School of Medicine, Duke University
- Duke Cancer Institute