Sphingosine‐1‐phosphate receptor 1 signalling in T cells: trafficking and beyond

Garris, Christopher; Blaho, Victoria A.; Hla, Timothy; Han, May

doi:10.1111/imm.12272

Cited by 126 publications

(155 citation statements)

References 67 publications

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“…A total of five subtypes of S1PRs (S1PR1-5) have been identified since the first S1PR was discovered by Hla T et al (1990). During the past two decades, S1P and its specific receptors were found to be involved in a wide range of pathophysiological processes (Maceyka et al, 2012) in multiple organ systems that include: the central nervous system, immune system (Soliven et al, 2011; Garris et al, 2014), cardiovascular system (Schmouder et al, 2012), and in embryonic development (Kondo et al, 2014; Hiraga et al, 2006). Further, emerging evidence indicates that S1P/S1PRs play significant roles in the proliferation, progression, survival and therapeutic response to treatment in cancer (Pyne et al, 2010; Kunkel et al, 2013; Pyne et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Systemic distribution, subcellular localization and differential expression of sphingosine-1-phosphate receptors in benign and malignant human tissues

Wang

Mao

Redfield

et al. 2014

Experimental and Molecular Pathology

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Aims Five sphingosine-1-phosphate receptors (S1PR): S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5 (S1PR1-5) have been shown to be involved in the proliferation and progression of various cancers. However, none of the S1PRs have been systemically investigated. In this study, we performed immunohistochemistry (IHC) for S1PR1-S1PR5 on different tissues, in order to simultaneously determine the systemic distribution, subcellular localization and expression level of all five S1PRs. Methods We constructed tissue microarrays (TMAs) from 384 formalin-fixed paraffin-embedded (FFPE) blocks containing 183 benign and 201 malignant tissues from 34 human organs/systems. Then we performed IHC for all five S1PRs simultaneously on these TMA slides. The distribution, subcellular localization and expression of each S1PR were determined for each tissue. The data were then compared in benign and malignant tissues from the same organ/tissue using the student t-test. In order to reconfirm the subcellular localization of each S1PR as determined by IHC, immunocytochemistry (ICC) was performed on several malignant cell lines. Results We found that all five S1PRs are widely distributed in multiple human organs/systems. All S1PRs are expressed in both the cytoplasm and nucleus, except S1PR3, whose IHC signals are only seen in the nucleus. Interestingly, the S1PRs are rarely expressed on cellular membranes. Each S1PR is unique in its organ distribution, subcellular localization and expression level in benign and malignant tissues. Among the five S1PRs, S1PR5 has the highest expression level (either in nucleus or cytoplasm), with S1PR1, 3, 2 and 4 following in descending order. Strong nuclear expression was seen for S1PR1, S1PR3 and S1PR5, whereas S1PR2 and S1PR4 show only weak staining. Four organs/tissues (adrenal gland, liver, brain and colon) show significant differences in IHC scores for the multiple S1PRs (nuclear and/or cytoplasmic), nine (stomach, lymphoid tissues, lung, ovary, cervix, pancreas, skin, soft tissues and uterus) show differences for only one S1PR (cytoplasmic or nuclear), and twenty three organs/tissues show no significant difference in IHC score of any S1PR (cytoplasmic or nuclear) between benign and malignant changes. Conclusion This is the first study to evaluate the expression level of all S1PRs in benign and malignant tissues from multiple human organs. This study provides data regarding the systemic distribution, subcellular localization and differences in expression of all five S1PRs in benign and malignant changes for each organ/tissue.

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Section: Introductionmentioning

confidence: 99%

Systemic distribution, subcellular localization and differential expression of sphingosine-1-phosphate receptors in benign and malignant human tissues

Wang

Mao

Redfield

et al. 2014

Experimental and Molecular Pathology

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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).…”

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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.

160

147

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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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“…Individuals from whom PA was never isolated in sputum show heightened PBMC transcription of the Th1-controlling transcription factor, Tbet, and the S1P1 receptor, implicated in both central nervous system and lung lymphocyte trafficking (47). A relative reduction in Tbet transcription in chronic infection may indicate an intrinsic defect in (or, at least, program bias away from) Th1 polarization.…”

Section: Original Article Discussionmentioning

confidence: 99%

Chronic Infection by Mucoid Pseudomonas aeruginosa Associated with Dysregulation in T-Cell Immunity to Outer Membrane Porin F

Quigley

Reynolds

Goudet

et al. 2015

Am J Respir Crit Care Med

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Rationale: Pseudomonas aeruginosa (PA) is an environmental pathogen that commonly infects individuals with cystic fibrosis (CF) and non-CF bronchiectasis, impacting morbidity and mortality. To understand the pathobiology of interactions between the bacterium and host adaptive immunity and to inform rational vaccine design, it is important to understand the adaptive immune correlates of disease.Objectives: To characterize T-cell immunity to the PA antigen outer membrane porin F (OprF) by analyzing immunodominant epitopes in relation to infection status.Methods: Patients with non-CF bronchiectasis were stratified by frequency of PA isolation. T-cell IFN-g immunity to OprF and its immunodominant epitopes was characterized. Patterns of human leukocyte antigen (HLA) restriction of immunodominant epitopes were defined using HLA class II transgenic mice. Immunity was characterized with respect to cytokine and chemokine secretion, antibody response, and T-cell activation transcripts. Measurements and Main Results:Patients were stratified according to whether PA was never, sometimes (,50%), or frequently (>50%) isolated from sputum. Patients with frequent PA sputumpositive isolates were more likely to be infected by mucoid PA, and they showed a narrow T-cell epitope response and a relative reduction in Th1 polarizing transcription factors but enhanced immunity with respect to antibody production, innate cytokines, and chemokines. Conclusions:We have defined the immunodominant, HLArestricted T-cell epitopes of OprF. Our observation that chronic infection is associated with a response of narrowed specificity, despite strong innate and antibody immunity, may help to explain susceptibility in these individuals and pave the way for better vaccine design to achieve protective immunity.

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Sphingosine‐1‐phosphate receptor 1 signalling in T cells: trafficking and beyond

Cited by 126 publications

References 67 publications

Systemic distribution, subcellular localization and differential expression of sphingosine-1-phosphate receptors in benign and malignant human tissues

Systemic distribution, subcellular localization and differential expression of sphingosine-1-phosphate receptors in benign and malignant human tissues

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

Chronic Infection by Mucoid Pseudomonas aeruginosa Associated with Dysregulation in T-Cell Immunity to Outer Membrane Porin F

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