Abstract
Sphingosine-1-phosphate (S1P), a lipid mediator, regulates lymphocyte migration between lymphoid tissue and blood. Furthermore, S1P participates in several physiological phenomena including angiogenesis, inflammation, immune regulation, and neurotransmitter release. Moreover, S1P/S1P receptor signaling involves in systemic sclerosis (SSc) pathogenesis. This study aimed to investigate whether the selective S1P1 receptor modulator cenerimod attenuates murine sclerodermatous models. Cenerimod was orally administered to murine sclerodermatous chronic graft versus host disease (Scl-cGVHD) mice, either from day 0 to 42 or day 22 to 42 after bone marrow transplantation. Bleomycin-induced SSc model mice were administered cenerimod from day 0 to 28. Early cenerimod administration inhibited, and delayed cenerimod administration attenuated skin and lung fibrosis in Scl-cGVHD mice. Cenerimod suppressed the infiltration of CD4+ T cells, CD8+ T cells, and CD11b+ cells into the inflamed skin of Scl-cGVHD mice as opposed to control mice. In contrast, cenerimod increased the frequency of regulatory T cells in the spleen and skin of Scl-cGVHD mice. Additionally, cenerimod attenuated the mRNA expression of extracellular matrix and fibrogenic cytokines in the skin. Furthermore, cenerimod attenuated bleomycin-induced fibrosis in the skin and lung. Hence, the selective S1P1 receptor modulator cenerimod is a promising candidate for treating patients with SSc and Scl-cGVHD.
Highlights
Systemic sclerosis (SSc) is a fibrotic disease characterized by immunologic abnormalities, vascular injury, and increased accumulation of extracellular matrix (ECM) proteins in the skin[1,2]
This study aimed to investigate the effect of the selective S1P1 receptor modulator cenerimod on murine Scl-cGVHD model and bleomycin-induced scleroderma model
This study is the first to evaluate the therapeutic effects of the selective S1P1 receptor modulator cenerimod on a murine Scl-cGVHD model and a bleomycin-induced scleroderma model
Summary
Systemic sclerosis (SSc) is a fibrotic disease characterized by immunologic abnormalities, vascular injury, and increased accumulation of extracellular matrix (ECM) proteins in the skin[1,2]. Regulation of lymphocytes is essential to treat SSc. Murine sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) is a well-established model for human Scl-cGVHD and human SSc7–9. Murine sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) is a well-established model for human Scl-cGVHD and human SSc7–9 It can be induced by bone marrow (BM) and splenocyte transplantation from B10.D2 mice (major histocompatibility complex haplotype H-2d) into sublethally irradiated BALB/c (H-2d) mice across minor histocompatibility loci; this recapitulates the prominent characteristics of human SSc10. Selective S1P1 receptor modulators may be potent therapeutic agents to treat SSc with fewer side effects. Selective, safe and orally administrable S1P1 receptor modulator, which reportedly reduced blood lymphocytes and attenuated murine experimental autoimmune encephalomyelitis (EAE) in a murine model[23,24]. This study aimed to investigate the effect of the selective S1P1 receptor modulator cenerimod on murine Scl-cGVHD model and bleomycin-induced scleroderma model
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