Sphingosine 1-phosphate signaling impacts lymphocyte migration, inflammation and infection

Tiper, Irina V.; East, James E.; Subrahmanyam, Priyanka B.; Webb, Tonya J.

doi:10.1093/femspd/ftw063

Cited by 39 publications

(26 citation statements)

References 86 publications

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“…Among a variety of factors that mediate switch BMMs to pro-inflammatory M1 phenotype, S1P is probably one of the most potent regulatory molecules [36]. S1P has been implicated in many key cellular processes, including cell proliferation, differentiation, migration and survival [37]. Besides, S1P acts as a crucial inflammatory mediator and can be released in response to inflammation and following injury [36,38].…”

Section: Discussionmentioning

confidence: 99%

“…These data are in agreement with recent studies highlighting a central role of S1P-induced immune cell polarization in many different cellular types including T cell, macrophage, and mast cell [46], further proving that S1P production is necessary for M1 polarization. Many studies have reported that polarization of immune cells appear to be mediated via the binding of S1P to S1P receptors [37]. However, S1P signaling is complex and may have both pro-and anti-inflammatory properties, especially for BMMs.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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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“…In the pivotal evaluation of nivolumab, the median time to response was 3.7 months. 19 There is the possibility that such effects could mitigate synergy with PD-1/PD-L1 inhibitors, which enhance the function of T lymphocytes; however, the otherwise immunostimulatory properties of sonepcizumab nonetheless make such combinations theoretically attractive. The phase 3 studies of nivolumab and cabozantinib in patients with mRCC allowed for up to 2 prior therapies and unlimited prior therapies, respectively.…”

Section: Discussionmentioning

confidence: 99%

A phase 2 study of the sphingosine‐1‐phosphate antibody sonepcizumab in patients with metastatic renal cell carcinoma

Pal

Drabkin

Reeves

et al. 2016

Cancer

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“…Consequently, S1PRs are considered candidate therapeutic targets for inflammatory diseases, including MS, psoriasis, asthma, and polyneuritis, and also for hematologic and solid tumors, ischemic stroke, and wound healing (7)(8)(9)(10)(11)(12). FTY720 (fingolimod) is a modulator of S1P receptors 1, 3, 4, and 5 with therapeutic effects on RRMS (13)(14)(15)(16)(17)(18).…”

mentioning

confidence: 99%

Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation

Rothhammer

Kenison

Tjon

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

171

156

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Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS that causes disability in young adults as a result of the irreversible accumulation of neurological deficits. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, these therapies show limited efficacy in secondary progressive MS (SPMS). Thus, there is an unmet clinical need for the identification of disease mechanisms and potential therapeutic approaches for SPMS. Here, we show that the sphingosine 1-phosphate receptor (S1PR) modulator fingolimod (FTY720) ameliorated chronic progressive experimental autoimmune encephalomyelitis in nonobese diabetic mice, an experimental model that resembles several aspects of SPMS, including neurodegeneration and disease progression driven by the innate immune response in the CNS. Indeed, S1PR modulation by FTY720 in murine and human astrocytes suppressed neurodegeneration-promoting mechanisms mediated by astrocytes, microglia, and CNS-infiltrating proinflammatory monocytes. Genome-wide studies showed that FTY720 suppresses transcriptional programs associated with the promotion of disease progression by astrocytes. The study of the molecular mechanisms controlling these transcriptional modules may open new avenues for the development of therapeutic strategies for progressive MS.multiple sclerosis | sphingolipid metabolism | astrocytes | EAE | secondary progression M ultiple sclerosis (MS) is a chronic autoimmune disease of the CNS that, in most patients, initially presents with a relapsing-remitting course. This relapsing-remitting stage is often followed by a secondary progressive phase characterized by the progressive and irreversible accumulation of neurological deficits. The available therapeutic approaches for relapsing-remitting MS (RRMS) show limited efficacy in secondary progressive MS (SPMS), reflecting our insufficient understanding of the pathologic mechanisms that drive disease progression in SPMS and primary progressive MS (1). Recent findings, however, suggest that the innate immune response in the CNS promotes disease progression in MS. Indeed, astrocytes (the most abundant cell population in the mammalian CNS), microglia, and proinflammatory monocytes are thought to promote neurodegeneration, demyelination, and scar formation (1-6). However, therapeutic strategies targeting these cell types remain elusive to date.Sphingosine 1-phosphate (S1P) is a sphingosine-containing lipid generated from ceramide, which binds G protein-coupled receptors [Sphingosine 1-phospate receptors (S1PRs) 1-5] and modulates the proliferation and trafficking of several cell types, including immune cells. Consequently, S1PRs are considered candidate therapeutic targets for inflammatory diseases, including MS, psoriasis, asthma, and polyneuritis, and also for hematologic and solid tumors, ischemic stroke, and wound healing (7-12). FTY720 (fingolimod) is a modulator of S1P receptors 1, 3, 4, and 5 with therapeutic effects on RRMS (13-18). The therapeutic effects of ...

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Sphingosine 1-phosphate signaling impacts lymphocyte migration, inflammation and infection

Cited by 39 publications

References 86 publications

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

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

A phase 2 study of the sphingosine‐1‐phosphate antibody sonepcizumab in patients with metastatic renal cell carcinoma

Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation

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