Chronic Toll-like receptor 4 stimulation in skin induces inflammation, macrophage activation, transforming growth factor beta signature gene expression, and fibrosis
Open accessAbstract
Introduction: The crucial role of innate immunity in the pathogenesis of systemic sclerosis (SSc) is well established, and in the past few years the hypothesis that Toll-like receptor 4 (TLR4) activation induced by endogenous ligands is involved in fibrogenesis has been supported by several studies on skin, liver, and kidney fibrosis. These findings suggest that TLR4 activation can enhance transforming growth factor beta (TGF-β) signaling, providing a potential mechanism for TLR4/Myeloid differentiation factor 88 (MyD88)-dependent fibrosis. Methods: The expression of TLR4, CD14 and MD2 genes was analyzed by real-time polymerase chain reaction from skin biopsies of 24 patients with diffuse cutaneous SSc. In order to investigate the effects of the chronic skin exposure to endotoxin (Lipopolysaccharide (LPS)) in vivo we examined the expression of inflammation, TGF-β signaling and cellular markers genes by nanostring. We also identified cellular subsets by immunohistochemistry and flow cytometry. Results: We found that TLR4 and its co-receptors, MD2 and CD14, are over-expressed in lesional skin from patients with diffuse cutaneous SSc, and correlate significantly with progressive or regressive skin disease as assessed by the Delta Modified Rodnan Skin Score. In vivo, a model of chronic dermal LPS exposure showed overexpression of proinflammatory chemokines, recruitment and activation of macrophages, and upregulation of TGF-β signature genes. Conclusions: We delineated the role of MyD88 as necessary for the induction not only for the early phase of inflammation, but also for pro-fibrotic gene expression via activation of macrophages. Chronic LPS exposure might be a model of early stage of SSc when inflammation and macrophage activation are important pathological features of the disease, supporting a role for innate immune activation in SSc skin fibrosis.
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Combining molecular imaging of fibrosis with single-cell genomics could improve patient diagnostics, staging, prognostication, stratification, and cohort enrichment, optimizing clinical trial design.
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From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [177]
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Fibrosis: from mechanisms to medicines
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Self-citation
- Authors
- Stifano, G., Affandi, A. J., Mathes, A. L., Rice, L. M., Nakerakanti, S., Nazari, B., Lee, J., Christmann, R. B., & Lafyatis, R.
- Affiliations
- Boston University (US)
- Corresponding author
- Stifano, Giuseppina
- Venue
- Arthritis Research & Therapy
- Published
- 2014-07-01
- Volume
- 16
- Issue
- 4
- Pages
- R136-R136
- ISSN
- 1478-6354 (ISSN-L)
- PMC
- PMC4227089
- OpenAlex
- W2154229444
- Cited by
- 86
- References
- 40
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 10 · 2018: 6 · 2017: 10 · 2016: 13 · 2015: 14
- FWCI
- 9.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Arthritis Research & Therapy (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR051089, T32AR007598, P30AR061271, P50AR060780)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- systemic sclerosis, diffuse cutaneous systemic sclerosis, TLR4, MyD88, skin fibrosis, macrophage activation, TGF-beta signaling, lipopolysaccharide, endotoxin, innate immunity, skin inflammation, chemokines, CD14, MD-2
- MeSH terms
- Animals, Fibrosis, Flow Cytometry, Humans, Immunohistochemistry, Inflammation, Macrophage Activation, Mice, Inbred C57BL, Scleroderma, Systemic, Skin, Transforming Growth Factor beta, Mice, Knockout, Toll-Like Receptor 4, Mice, Myeloid Differentiation Factor 88, Transcriptome, Real-Time Polymerase Chain Reaction
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