Sphingosine-1-Phosphate receptor 5 modulates early-stage processes during fibrogenesis in a mouse model of systemic sclerosis : a pilot study

Systemic sclerosis (SSc) is a rare multi-organ autoimmune disease characterized by progressive skin fibrosis. Inflammation, type 2 immunity, and fibrogenic processes are involved in disease development and may be affecte
Systemic sclerosis (SSc) is a rare multi-organ autoimmune disease characterized by progressive skin fibrosis. Inflammation, type 2 immunity, and fibrogenic processes are involved in disease development and may be affected by sphingolipids. However, details about early-stage pathophysiological mechanisms and implicated mediators remain elusive. The sphingolipid sphingosine-1-phosphate (S1P) is elevated in the sera of SSc patients, and its receptor S1P5 is expressed in skin tissue. Nevertheless, almost nothing is known about the dermatological contribution of S1P5 to inflammatory and pro-fibrotic processes leading to the pathological changes seen in SSc. In this study, we observed a novel effect of S1P5 on the inflammatory processes during low-dose bleomycin (BLM)-induced fibrogenesis in murine skin. By comparing 2-week-treated skin areas of wild-type (WT) and S1P5-deficient mice, we found that S1P5 is important for the transcriptional upregulation of the Th2 characteristic transcription factor GATA-3 under treatment-induced inflammatory conditions, while T-bet (Th1) and FoxP3 (Treg) mRNA expression was regulated independently of S1P5. Additionally, treatment caused a regulation of S1P receptor 1 and S1P receptor 3 mRNA as well as a regulation of long-chain ceramide profiles, which both differ significantly between the genotypes. Despite S1P5-dependent differences regarding inflammatory processes, similar macroscopic evidence of fibrosis was detected in the skin histology of WT and S1P5-deficient mice after 4 weeks of subcutaneous BLM treatment. However, at the earlier 2-week point in time, the mRNA data of pro-collagen type 1 and SMAD7 indicate a pro-fibrotic S1P5 contribution in the applied SSc mouse model. In conclusion, we propose that S1P5 plays a role as a novel modulator during the early phase of BLM-caused fibrogenesis in murine skin. An immediate relationship between dermal S1P5 expression and fibrotic processes leading to skin alterations, such as formative for SSc pathogenesis, is indicated but should be studied more profound in further investigations. Therefore, this study is an initial step in understanding the role of S1P5-mediated effects during early stages of fibrogenesis, which may encourage the ongoing search for new therapeutic options for SSc patients.
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Author:Katrin G. Schmidt, Martina Herrero San Juan, Sandra Trautmann, Lucija Berninger, Anja Schwiebs, Florian Ottenlinger, Dominique Jeanette Thomas, Frank Zaucke, Josef Martin Pfeilschifter, Heinfried Hermann Radeke
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=29033951
Parent Title (English):Frontiers in immunology
Publisher:Frontiers Media
Place of publication:Lausanne
Contributor(s):Rudolf Lucas
Document Type:Article
Year of Completion:2017
Date of first Publication:2017/09/29
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2017/11/21
Tag:bleomycin; fibrogenesis; inflammation; mouse model; sphingolipid sphingosine-1-phosphate; sphingolipids; sphingosine-1-phosphate receptor 5; systemic sclerosis
Issue:Art. 1242
First Page:1
Last Page:13
Copyright © 2017 Schmidt, Herrero San Juan, Trautmann, Berninger, Schwiebs, Ottenlinger, Thomas, Zaucke, Pfeilschifter and Radeke. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
HeBIS PPN:425294609
Dewey Decimal Classification:610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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