ArticleArthritis research & therapy2020
TGFβ-mediated expression of TGFβ-activating integrins in SSc monocytes: disturbed activation of latent TGFβ?
Article in Arthritis research & therapy, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 22 citations in OpenAlex.
- Evidence of an allostatic response by intestinal tissues following induction of joint inflammation.PloS one · 2026Article
- The immune landscape of systemic sclerosis: from pathogenic mechanisms to precision therapeutic breakthroughs.Frontiers in immunology · 2026Review
- The Function of the TGFβ Signaling Pathway in Connective Tissue Diseases: From Biology to Clinical Application.Journal of inflammation research · 2025Review
- Dietary nucleic acids promote oral tolerance through innate sensing pathways in mice.Nature communications · 2024Article
- Dimension reduction, cell clustering, and cell-cell communication inference for single-cell transcriptomics with DcjComm.Genome biology · 2024Article
- Overcoming Vemurafenib Resistance in Metastatic Melanoma: Targeting Integrins to Improve Treatment Efficacy.International journal of molecular sciences · 2024Article
- Potential Roles of Activin in Head and Neck Squamous Cell Carcinoma Progression and Mortality.Anticancer research · 2023Article
- Three Distinct Transcriptional Profiles of Monocytes Associate with Disease Activity in Scleroderma Patients.Arthritis & rheumatology (Hoboken, N.J.) · 2023Article
- Reprogramming alveolar macrophage responses to TGF-β reveals CCR2+ monocyte activity that promotes bronchiolitis obliterans syndrome.The Journal of clinical investigation · 2022Article
- Specificity of TGF-β1 signal designated by LRRC33 and integrin αNature communications · 2022Article
- Human Keratinocytes Inhibit CD4Cells · 2021Article
- An overview of bio-actuation in collagen hydrogels: a mechanobiological phenomenon.Biophysical reviews · 2021Review
- Serum IGFBP-2 in systemic sclerosis as a prognostic factor of lung dysfunction.Scientific reports · 2021Article
- On-Target Anti-TGF-β Therapies Are Not Succeeding in Clinical Cancer Treatments: What Are Remaining Challenges?Frontiers in cell and developmental biology · 2020Review
- Integrin, Exosome and Kidney Disease.Frontiers in physiology · 2020Review
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionThe pathophysiology of systemic sclerosis (SSc) is closely linked to overactive TGFβ signaling. TGFβ is produced and circulates in latent form, making its activation crucial for signaling. This activation can be mediated via integrins. We investigated the balance between active and latent TGFβ in serum of SSc patients and investigated if this correlates with integrin expression on monocytes.
methodsA TGFβ/SMAD3- or BMP/SMAD1/5-luciferase reporter construct was expressed in primary human skin fibroblasts. Both acidified and non-acidified sera of ten SSc patients and ten healthy controls were tested on these cells to determine total and active TGFβ and BMP levels respectively. A pan-specific TGFβ1/2/3 neutralizing antibody was used to confirm TGFβ signaling. Monocytes of 20 SSc patients were isolated using CD14+ positive selection, and integrin gene expression was measured using qPCR. Integrin expression was modulated using rhTGFβ1 or a small molecule inhibitor of TGFBR1: SB-505124.
resultsSSc sera induced 50% less SMAD3-reporter activity than control sera. Serum acidification increased reporter activity, but a difference between healthy control and SSc serum was no longer observed, indicating that total TGFβ levels were not different. Addition of a pan-specific TGFβ1/2/3 neutralizing antibody fully inhibited SMAD3-reporter activity of both acidified and not-acidified control and SSc sera. Both HC and SSc sera induced similar SMAD1/5-reporter activity, and acidification increased this, but not differently between groups. Interestingly, expression of two integrin alpha subunits ITGA5 and ITGAV was significantly reduced in monocytes obtained from SSc patients. Furthermore, ITGB3, ITGB5, and ITGB8 expression was also reduced in SSc monocytes. Stimulation of monocytes with TGFβ1 induced ITGA5 and ITGAV but lowered ITGB8 expression, whereas the use of the TGFβ receptor inhibitor SB-505124 had the opposite effect.
conclusionTotal TGFβ serum levels are not different between SSc patients and controls, but TGFβ activity is. This coincides with a reduced expression of TGFβ-activating integrins in monocytes of SSc patients. Because TGFβ regulates expression of these integrins in monocytes, a negative feedback mechanism possibly underlies these observations.
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