Inhibiting Sphingosine Kinase 2 Derived-sphingosine-1-phosphate Ameliorates Psoriasis-like Skin Disease via Blocking Th17 Differentiation of Naïve CD4 T Lymphocytes in Mice

Shin, Sun Hye; Cho, Kyung Ah; Hahn, Soojung; Lee, Younghay; Kim, Yu‐Hee; Woo, So Youn; Ryu, Kyung Ha; Park, Woo Jae; Park, Joo Won

doi:10.2340/00015555-3160

Cited by 33 publications

(42 citation statements)

References 37 publications

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“…The role of S1P and its receptor in skin inflammation is very well discussed in the literature, albeit, not in the context of this study [34]. S1P and its receptors are exploited in terms of regulating either T cell infiltration [35] into inflamed skin or attenuating antigen presentation by skin DCs to T cells in the lymph node. In addition, S1P directly affects keratinocyte differentiation, which is beneficial during the recovery phase of psoriasis.…”

Section: Discussionmentioning

confidence: 99%

Macrophage S1PR1 Signaling Alters Angiogenesis and Lymphangiogenesis During Skin Inflammation

Syed

Raue

Weigert

et al. 2019

Cells

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The bioactive lipid sphingosine-1-phosphate (S1P), along with its receptors, modulates lymphocyte trafficking and immune responses to regulate skin inflammation. Macrophages are important in the pathogenesis of psoriasiform skin inflammation and express various S1P receptors. How they respond to S1P in skin inflammation remains unknown. We show that myeloid specific S1P receptor 1 (S1PR1) deletion enhances early inflammation in a mouse model of imiquimod-induced psoriasis, without altering the immune cell infiltrate. Mechanistically, myeloid S1PR1 deletion altered the formation of IL-1β, VEGF-A, and VEGF-C, and their receptors’ expression in psoriatic skin, which subsequently lead to reciprocal regulation of neoangiogenesis and neolymphangiogenesis. Experimental findings were corroborated in human clinical datasets and in knockout macrophages in vitro. Increased blood vessel but reduced lymph vessel density may explain the exacerbated inflammatory phenotype in conditional knockout mice. These findings assign a novel role to macrophage S1PR1 and provide a rationale for therapeutically targeting local S1P during skin inflammation.

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Section: Discussionmentioning

confidence: 99%

Macrophage S1PR1 Signaling Alters Angiogenesis and Lymphangiogenesis During Skin Inflammation

Syed

Raue

Weigert

et al. 2019

Cells

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“…has been reported in several previous studies (14,15); however, to the best of our knowledge, the expression and function of Sphk2 in HS has yet to be elucidated. in the present study, it was initially found that Sphk2 was upregulated, but Smad7 was downregulated in HS tissues compared with healthy skin tissues.…”

Section: Discussionmentioning

confidence: 78%

“…HS is a fibrotic disease characterized by the over-proliferation and activation of fibroblasts, which is often considered as a benign skin tumor ( 20 ). The role of Sphk2 in skin diseases has been reported in several previous studies ( 14 , 15 ); however, to the best of our knowledge, the expression and function of Sphk2 in HS has yet to be elucidated. In the present study, it was initially found that Sphk2 was upregulated, but Smad7 was downregulated in HS tissues compared with healthy skin tissues.…”

Section: Discussionmentioning

confidence: 82%

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Inhibition of sphingosine kinase 2 attenuates hypertrophic scar formation via upregulation of Smad7 in human hypertrophic scar fibroblasts

et al. 2020

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The aims of the present study were to investigate the role of sphingosine kinase 2 (Sphk2) in hypertrophic scar (HS) formation and its underlying mechanisms. The expression levels of Sphk2 and Smad7 in HS tissues and healthy skin tissues of patients undergoing plastic surgery were determined using immunohistochemical staining. Subsequently, the expression levels of Sphk2 and collagen i in human embryonic skin fibroblasts (control) and human HS fibroblasts (HSF) were detected using western blot analysis and immunofluorescence assay, respectively. Following Sphk2 silencing, Smad7 overexpression or both Sphk2 and Smad7 silencing, HSF proliferative ability was assessed using cell counting Kit-8 assay and proliferation-associated proteins were evaluated using western blot analysis. in addition, the level of apoptosis in HSF was assessed using flow cytometry and expression levels of apoptotic-associated proteins were determined using western blotting. Furthermore, the expression levels of collagen i and proteins in the TGF-β1/Smad signaling pathway were detected using western blot analysis. The results indicated that the expression of Sphk2 was significantly increased, while Smad7 expression was decreased in HS tissue. Moreover, the upregulation of Sphk2 and collagen i expression levels was identified in HSF. The present results also indicated that Sphk2 silencing or Smad7 overexpression inhibited proliferation, but promoted apoptosis of HSF, coupled with changes in the expression levels of proliferation-associated proteins, with an increase in p21 and a decrease in cyclin d1 expression levels, and apoptosis-associated proteins, with an increase in Bax and cleaved caspase-3, and a decrease in Bcl-2, which were reversed following transfection with both Sphk2 and Smad7 using small interfering rna in HSF. in addition, the expression levels of transforming growth factor-β1, phosphorylated (p)-Smad2, p-Smad3 and collagen i were reduced following Sphk2 silencing or Smad7 overexpression, which were abolished by silencing both Sphk2 and Smad7. collectively, the present results indicated that inhibition of Sphk2 attenuated HS formation via upregulation of Smad7 expression, thus Sphk2 may serve as a potential therapeutic target for the treatment of HS.

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“…In our study, PC and PS had lower concentrations in the IMQ-induced groups, but which were up-regulated by (R)-salbutamoltreatment, indicating that (R)-salbutamol conferred anti-psoriatic effects by modulating the metabolism of glycerophospholipid. Several studies [51][52][53] have reported the importance of sphingolipids in innate immunity regulation, especially in T cells differentiation and programming. Our results discovered that (R)-salbutamol against IMQ induced psoriasis by regulates the Th17/Treg axis.…”

Section: Discussionmentioning

confidence: 99%

(R)-Salbutamol Improves Imiquimod-Induced Psoriasis-Like Skin Dermatitis by Regulating the Th17/Tregs Balance and Glycerophospholipid Metabolism

Liu

Wang

Liu

et al. 2020

Cells

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Psoriasis is a skin disease that is characterized by a high degree of inflammation caused by immune dysfunction. (R)-salbutamol is a bronchodilator for asthma and was reported to alleviate immune system reactions in several diseases. In this study, using imiquimod (IMQ)-induced mouse psoriasis-like dermatitis model, we evaluated the therapeutic effects of (R)-salbutamol in psoriasis in vivo, and explored the metabolic pathway involved. The results showed that, compared with IMQ group, (R)-salbutamol treatment significantly ameliorated psoriasis, reversed the suppressive effects of IMQ on differentiation, excessive keratinocyte proliferation, and infiltration of inflammatory cells. Enzyme-linked immunosorbent assays (ELISA) showed that (R)-salbutamol markedly reduced the plasma levels of IL-17. Cell analysis using flow cytometry showed that (R)-salbutamol decreased the proportion of CD4+ Th17+ T cells (Th17), whereas it increased the percentage of CD25+ Foxp3+ regulatory T cells (Tregs) in the spleens. (R)-salbutamol also reduced the increased weight ratio of spleen to body. Furthermore, untargeted metabolomics showed that (R)-salbutamol affected three metabolic pathways, including (i) arachidonic acid metabolism, (ii) sphingolipid metabolism, and (iii) glycerophospholipid metabolism. These results demonstrated that (R)-salbutamol can alleviate IMQ-induced psoriasis through regulating Th17/Tregs cell response and glycerophospholipid metabolism. It may provide a new use of (R)-salbutamol in the management of psoriasis.

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Inhibiting Sphingosine Kinase 2 Derived-sphingosine-1-phosphate Ameliorates Psoriasis-like Skin Disease via Blocking Th17 Differentiation of Naïve CD4 T Lymphocytes in Mice

Cited by 33 publications

References 37 publications

Macrophage S1PR1 Signaling Alters Angiogenesis and Lymphangiogenesis During Skin Inflammation

Macrophage S1PR1 Signaling Alters Angiogenesis and Lymphangiogenesis During Skin Inflammation

Inhibition of sphingosine kinase 2 attenuates hypertrophic scar formation via upregulation of Smad7 in human hypertrophic scar fibroblasts

(R)-Salbutamol Improves Imiquimod-Induced Psoriasis-Like Skin Dermatitis by Regulating the Th17/Tregs Balance and Glycerophospholipid Metabolism

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