Attenuation of murine sclerodermatous models by the selective S1P1 receptor modulator cenerimod

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.

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.…”

Suppression of IL-23-mediated psoriasis-like inflammation by regulatory B cells

“…Sections were stained with hematoxylin and eosin (H&E). As we described previously in our study 42 , for immunohistochemical (IHC) staining of CD4 and CD8, the sections were frozen in Tissue-Tek OCT compound (Sakura Finetek, Tokyo, Japan) and quickly frozen in liquid nitrogen. Frozen sections were fixed in cold acetone for 5 min and incubated with rat mAbs specific for mouse CD4 (RM4–5 clone; BD Biosciences, San Jose, CA, USA) and CD8 (53–6.7 clone; BD Biosciences).…”

Sphingosine 1-Phosphate Signaling at the Skin Barrier Interface

“…IMMH002, a recently developed oral S1PR1 modulator, reduces irritation in the SDS-induced psoriasis-like skin lesion mouse model, T lymphocyte infiltration of the imiquimod-induced psoriasiform dermatitis mouse model, and skin damage in the propranolol-induced psoriasis-like skin lesion guinea pig model [ 92 ]. Another S1PR1 modulator, cenerimod, reduces skin and lung fibrosis in a bleomycin-induced SSc mouse model [ 12 ].…”

“…The functions of S1P and the S1P-S1PR signaling pathway are equally important in the skin organ. They are involved in keratinocyte differentiation and proliferation [ 5 , 6 ], mast cell degranulation and migration [ 7 , 8 ], and have been shown to contribute to the pathogenesis of skin sclerosis, psoriasis, and atopic dermatitis, as well as in the defense of bacterial infections [ 9 , 10 , 11 , 12 , 13 , 14 ].…”