Sphingosine-1-Phosphate Receptor 5 Modulates Early-Stage Processes during Fibrogenesis in a Mouse Model of Systemic Sclerosis: A Pilot Study

Abstract

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.

The S1P–S1PR Axis in Neurological Disorders—Insights into Current and Future Therapeutic Perspectives

“…It may be advised, under some conditions, to exploit multiple S1PR pathways. S1P 5 , for example, is implicated in having pro-fibrotic effects to act on proliferation and its involvement in early transforming-growth-factor-β (TGF-β)-signaling [283]. Therefore, fibrotic conditions or tissue scarring might be well-suited for treatment with an agent synthesized to evoke agonistic effects both against S1P 1 and S1P 5 .…”

Genetic Interactions Affect Lung Function in Patients with Systemic Sclerosis

“…This signaling phospholipid is elevated in the serum of SSc individuals and is capable of producing many of the abnormalities seen in SSc (Pattanaik and Postlethwaite 2010;Tokumura et al 2009). Sphingosine-1-Phosphate Receptor 5 was found to modulate early fibrogenesis in a mouse model of SSc (Schmidt et al 2017), and the selective S1P1 receptor modulator cenerimod has been shown to attenuate lung and skin fibrosis in two different mouse models of SSc (Kano et al 2019). FARP2 encodes FERM, RhoGEF and pleckstrin domain protein 2 and is involved in semaphorin signaling.…”

The Effect of Lipid Metabolism on CD4+ T Cells

“…S1P significantly reduces the number of CD4 + T and Th17 cells [ 69 ], but it does not affect Th1 cell differentiation. However, the detail mechanism how S1P regulates T cell differentiation is still unknown [ 70 ].…”