Sphingosine‐1‐phosphate modulators in inflammatory skin diseases – lining up for clinical translation

Thieme, Markus; Zillikens, Detlef; Sadik, Christian D.

doi:10.1111/exd.13174

Cited by 15 publications

(12 citation statements)

References 75 publications

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“…We studied another BA receptor S1PR2, which regulates lipid and sterol metabolism in the liver and also modulates inflammatory skin disease [36]. To monitor S1PR2 signaling, we assessed the expression of S1pr2, sphingosine kinase isoenzymes (Sphk1, Sphk2), S1P phosphatase 1 and 2 (Sgpp1, Sgpp2), S1P binding protein, i.e., prohibitin 2 (Phb2), as well as S1P transporter (Spns2) in the cutaneous and adipose tissues.…”

Section: Effect Of Diet and Dermatitis Development On S1pr2 Signalingmentioning

confidence: 99%

Long-term Western diet intake leads to dysregulated bile acid signaling and dermatitis with Th2 and Th17 pathway features in mice

Jena

Sheng

McNeil

et al. 2019

Journal of Dermatological Science

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Background: Dietary interventions are implicated in the development of atopic dermatitis, psoriasis, and acne. Objective: To investigate the effect of diet and the bile acid (BA) receptors, such as TGR5 (Takeda G protein receptor 5) and S1PR2 (sphingosine-1-phosphate receptor 2) in the development of dermatitis. Methods: C57BL/6 mice were fed a control diet (CD) or Western diet (WD) since weaning until they were 10 months old followed by analyzing histology, gene expression, and BA profiling. Results: Mice developed dermatitis as they aged and the incidence was higher in females than males. Additionally, WD intake substantially increased the incidence of dermatitis. Cutaneous antimicrobial peptide genesS100A8, S100A9, and Defb4 were reduced in WD-fed mice, but increased when mice developed skin lesions. In addition, Tgr5 and TGR5-regulated Dio2 and Nos3 were reduced in WD intake but induced in dermatitic lesions. Trpa1 and Trpv1, which mediate itch, were also increased in dermatitic lesions. The expression of S1pr2 and genes encoding sphingosine kinases, S1P phosphatases, binding protein, and transporter were all reduced by WD intake but elevated in dermatitic lesions. Furthermore, dermatitis development increased total cutaneous BA with an altered profile, which may change TGR5 and S1PR2 activity. Moreover, supplementation with BA sequestrant cholestyramine reduced epidermal thickening as well as cutaneous inflammatory cytokines. Conclusion: In summary, activation of TGR5 and S1PR2, which regulate itch, keratinocyte proliferation, metabolism, and inflammation, may contribute to WD-exacerbated dermatitis with Th2 and Th17 features. In addition, elevated total BA play a significant role in inducing dermatitis and cutaneous inflammation.

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Section: Effect Of Diet and Dermatitis Development On S1pr2 Signalingmentioning

confidence: 99%

Long-term Western diet intake leads to dysregulated bile acid signaling and dermatitis with Th2 and Th17 pathway features in mice

Jena

Sheng

McNeil

et al. 2019

Journal of Dermatological Science

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“…Recently, increasing evidence demonstrate that S1P is involved in the progression of various inflammatory-related diseases such as inflammatory bowel disease [14], inflammatory skin diseases [15] and rheumatoid arthritis [16]. Of note, S1P exerts different cellular functions via its receptors or as a cell second messenger [17].…”

Section: Introductionmentioning

confidence: 99%

Sphingosine 1-Phosphate (S1P)/S1P Receptor2/3 Axis Promotes Inflammatory M1 Polarization of Bone Marrow-Derived Monocyte/Macrophage via G(α)i/o/PI3K/JNK Pathway

Yang¹,

Yang²,

Tian³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Macrophages, the most plastic cells in the haematopoietic system, are found in all tissues and show great functional heterogeneity. Sphingosine 1-phosphate (S1P)/ S1P receptors (S1PRs) system is widely involved in the process of inflammatory disease, whereas little evidence concerning its role in functional macrophage polarization is available. Thus, the present study was designed to evaluate the effects of S1P/S1PRs on functional polarization of macrophage in mouse bone marrow (BM)-derived monocyte/macrophages (BMMs). Methods: For the detection of M1 macrophage markers, such as CD86, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1/ chemokine (C-C motif) ligand (CCL) 2, nitric oxide synthase (NOS) 2, and macrophage inflammatory protein (MIP)-1β, RT-qPCR and cytometric bead array (CBA) were performed in cultured primary BMMs after the treatment with selective S1PR_2/3 antagonists or specific S1PRs siRNA. Western blotting and immunofluorescence were used for the detection of phosphorylation of JNK1/2. Results: BMMs expressed S1PR_1-3 and interestingly, S1PR_2/3, but not S1PR₁, mediates S1P-induced M1 macrophage polarization of BMMs as their siRNA or antagonists reduced M1 genes’ expression. We found that PTX (inhibitor of G(α)_i/o), LY294002 (inhibitor of PI3K) or SP600125 (inhibitor of JNK1/2) prevented up-regulation of M1 genes expression mediated by S1P/S1PR_2/3 signal, and S1P-induced JNK phosphorylation was inhibited by antagonists of S1PR_2/3, PTX or LY294002. Conclusion: Collectively, our results demonstrate that S1P/S1PR_2/3 plays a key role in regulating M1 type polarization of BMMs and acts by activating G(α)_i/o/PI3K/JNK signaling pathway, with potential implications for new approaches to inflammatory liver disease therapy.

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“…There is evidence 91 supporting both protective and pathogenic effects of S1P signaling in mouse and human chronic itch and 92 inflammatory diseases. In humans, elevated serum S1P is correlated with disease severity in both 93 psoriasis and systemic sclerosis (Castelino and Varga, 2014;Checa et al, 2015;Thieme et al, 2017). 94 Furthermore, ponesimod, an S1PR modulator and blocker of S1P signaling, appears to be promising for 95 psoriasis treatment in humans (Brossard et al, 2013;Vaclavkova et al, 2014;Krause et al, 2017).…”

mentioning

confidence: 99%

S1PR3 mediates itch and pain via distinct TRP channel-dependent pathways

Hill

Morita

Brem

et al. 2017

Preprint

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Sphingosine‐1‐phosphate modulators in inflammatory skin diseases – lining up for clinical translation

Cited by 15 publications

References 75 publications

Long-term Western diet intake leads to dysregulated bile acid signaling and dermatitis with Th2 and Th17 pathway features in mice

Long-term Western diet intake leads to dysregulated bile acid signaling and dermatitis with Th2 and Th17 pathway features in mice

Sphingosine 1-Phosphate (S1P)/S1P Receptor2/3 Axis Promotes Inflammatory M1 Polarization of Bone Marrow-Derived Monocyte/Macrophage via G(α)i/o/PI3K/JNK Pathway

S1PR3 mediates itch and pain via distinct TRP channel-dependent pathways

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