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.
Highlights
Systemic sclerosis (SSc, known as scleroderma) is a rare multi-organ autoimmune disease with a complex pathophysiology, characterized by microvascular damage, deregulated immunity, and fibrosis
Our results clearly demonstrate that low-dose bleomycin (BLM) induces S1P receptor 5 (S1P5)-dependent variations in cutaneous Cer and GluCer profiles, as well as a transcriptional upregulation of inflammation-associated factors like Th2 transcription factor GATA binding protein 3 (GATA-3) and S1P3, as well as pro-fibrotic collagen type I alpha 1 (COL1A1) in the early sclerotic phase
To generate an inflammatory milieu in the skin contributing to fibrosis, repetitive subcutaneous injections of low-dose BLM (25 μg/day; 5 days/week) either for a period of 2 or 4 weeks were applied in a mouse model of scleroderma
Summary
Systemic sclerosis (SSc, known as scleroderma) is a rare multi-organ autoimmune disease with a complex pathophysiology, characterized by microvascular damage, deregulated immunity, and fibrosis. Skin fibrosis is one important hallmark of SSc and especially the extent of skin involvement and its rate of progression reveal the severity of internal organ complications [3, 4]. Expansion of connective tissue, and resulting tissue dysfunctions are the consequence of remodeling processes with an excessive deposition of extracellular matrix components such as type I collagen [2, 5]. Overexpressed COMP assists skin-fibrotic SSc features in two ways: intracellular COMP auxiliary collagen secretion, while extracellular COMP acts as crosslinker between collagen I and collagen XII and its presence results in a more compact extracellular matrix network [10,11,12,13]
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