Acid sphingomyelinase deficiency contributes to resistance of scleroderma fibroblasts to Fas-mediated apoptosis
Open accessAbstract
Background Scleroderma (SSc) is characterized by excess production and deposition of extracellular matrix (ECM) proteins. Activated fibroblasts play a key role in fibrosis in SSc and are resistant to Fas-mediated apoptosis. Acid sphingomyelinase (ASMase), a major sphingolipid enzyme, plays an important role in the Fas-mediated apoptosis.Objective We investigated whether dysregulation of ASMase contributes to Fas-mediated apoptosis resistance in SSc fibroblasts.Methods Fibroblasts were isolated from SSc patients and healthy controls. Western blot was performed to analyze protein levels and quantitative real time RT-PCR was used to determine mRNA expression. Cells were transiently transfected with siRNA oligos against ASMase or transduced with adenoviruses overexpressing ASMase. Apoptosis was induced using anti-Fas antibody (1 μg/mL) and analyzed using caspase-3 antibody or Cell Death Detection ELISA.Results SSc fibroblasts showed increased resistance to Fas-mediated apoptosis. ASMase expression was decreased in SSc fibroblasts and Transforming Growth Factor beta (TGFβ), the major fibrogenic cytokine involved in the pathogenesis of SSc, downregulated ASMase in normal fibroblasts. Forced expression of ASMase in SSc fibroblasts restored sensitivity of these cells to Fas-mediated apoptosis while blockade of ASMase was sufficient to induce partial resistance to Fas-induced apoptosis in normal fibroblasts. In addition, ASMase blockade decreased activity of protein phosphatase 2A (PP2A) through phosphorylation on Tyr(307) and resulted in activation of extracellular regulated kinase 1/2 (Erk1/2) and protein kinase B (Akt/PKB).Conclusion In conclusion, this study suggests that ASMase deficiency promotes apoptosis resistance and contributes to activation of profibrotic signaling in SSc fibroblasts.
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TGFβ lowers expression of SMPD1; reduction in SMPD1 enhances pro-survival AKT signaling and reduces Fas-dependent apoptosis.
“Furthermore, TGFβ signaling also lowers expression of acid sphingomyelinase (SMPD1) (39). This enzyme induces the activation of protein phosphatase 2 (PP2A), i.e., an inhibitor of AKT signaling, and a reduction in SMPD1 thus enhances pro-survival AKT signaling. Additionaly, SMPD1 facilitates Fas-dependent apoptosis via its product; i.e., the lipid ceramide, which helps cluster Fas at the cell mem”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [39]
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Unraveling SSc Pathophysiology; The Myofibroblast
van Caam, A., Vonk, M., van den Hoogen, F., van Lent, P., & van der Kraan, P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02452 · Cited by 153 · see citing works
- Authors
- Samuel, G. H., Lenna, S., Bujor, A. M., Lafyatis, R., & Trojanowska, M.
- Affiliations
- Boston University (US)
- Corresponding author
- Trojanowska, Maria
- Venue
- Journal of Dermatological Science
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 67
- Issue
- 3
- Pages
- 166-172
- ISSN
- 0923-1811 (ISSN-L)
- PMC
- PMC3423203
- OpenAlex
- W2085215491
- Cited by
- 22
- References
- 31
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 2 · 2014: 1 · 2013: 2
- FWCI
- 0.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Dermatological Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Medical University of South Carolina
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R56AR044883, AR 44883, R01AR051089, P50AR060780, R01AR044883)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- systemic sclerosis, acid sphingomyelinase, Fas-mediated apoptosis, apoptosis resistance, fibroblasts, fibrosis, sphingolipid metabolism, TGF-beta, protein phosphatase 2A, ERK1/2, Akt signaling, caspase-3
- MeSH terms
- Extracellular Matrix, Fibroblasts, Fibrosis, Humans, Oligonucleotides, Scleroderma, Systemic, Sphingomyelin Phosphodiesterase, Wound Healing, Cytokines, Transforming Growth Factor beta, Apoptosis, fas Receptor, RNA Interference, RNA, Small Interfering, Extracellular Signal-Regulated MAP Kinases, Niemann-Pick Disease, Type A, Protein Phosphatase 2, Myofibroblasts
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