Activation of JUN in fibroblasts promotes pro-fibrotic programme and modulates protective immunity
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Abstract
The transcription factor JUN is highly expressed in pulmonary fibrosis. Its induction in mice drives lung fibrosis, which is abrogated by administration of anti-CD47. Here, we use high-dimensional mass cytometry to profile protein expression and secretome of cells from patients with pulmonary fibrosis. We show that JUN is activated in fibrotic fibroblasts that expressed increased CD47 and PD-L1. Using ATAC-seq and ChIP-seq, we found that activation of JUN rendered promoters and enhancers of CD47 and PD-L1 accessible. We further detect increased IL-6 that amplified JUN -mediated CD47 enhancer activity and protein expression. Using an in vivo mouse model of fibrosis, we found two distinct mechanisms by which blocking IL-6, CD47 and PD-L1 reversed fibrosis, by increasing phagocytosis of profibrotic fibroblasts and by eliminating suppressive effects on adaptive immunity. Our results identify specific immune mechanisms that promote fibrosis and suggest a therapeutic approach that could be used alongside conventional anti-fibrotics for pulmonary fibrosis.
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Various critical transcription factors, including HIF-1α, c-MYC, NF-kB, STAT3, c-JUN, and miR-138-5p, have been shown to transcriptionally regulate PD-L1 expression.
“Various critical transcription factors, including HIF-1α, c-MYC, NF-kB, STAT3, c-JUN, and miR-138-5p have been shown to transcriptionally regulate PD-L1 expression25–30.”
From PRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells (2022) · cites this paper as [29]
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References 63 · Cited by 153
- Authors
- Cui, L., Chen, S.-Y., Lerbs, T., Lee, J.-W., Domizi, P., Gordon, S., Kim, Y.-H., Nolan, G., Betancur, P., & Wernig, G.
- Affiliations
- Stanford Medicine (US)
- Institute of Biomedical Sciences, Academia Sinica (TW)
- University of California, San Francisco (US)
- Corresponding author
- Wernig, Gerlinde
- ORCID
- Venue
- Nature Communications
- Published
- 2020-06-03
- Volume
- 11
- Issue
- 1
- Pages
- 2795-2795
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7270081
- OpenAlex
- W3029242248
- Cited by
- 153
- References
- 63
- Citations by year
- 2026: 15 · 2025: 28 · 2024: 33 · 2023: 19 · 2022: 21 · 2021: 31 · 2020: 4 · 2015: 1
- FWCI
- 10.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Scleroderma Research Foundation (SPO 134886)
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (SPO 132801)
- Boehringer Ingelheim (SPO 136135)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Keywords
- JUN transcription factor, pulmonary fibrosis, fibroblasts, CD47, PD-L1, interleukin-6, enhancer accessibility, phagocytosis, adaptive immunity, fibroblast secretome, antifibrotic therapy
- MeSH terms
- Animals, Fibroblasts, Humans, Immunity, Immunosuppression Therapy, Macrophages, Phenotype, Pulmonary Fibrosis, T-Lymphocytes, Interleukin-6, Proto-Oncogene Proteins c-jun, Bronchoalveolar Lavage, Mice, CD47 Antigen, B7-H1 Antigen
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