Single-cell profiling reveals GPCR heterogeneity and functional patterning during neuroinflammation

Tischner, Denise; Grimm, Myriam; Kaur, Harmandeep; Staudenraus, Daniel; Carvalho, Jorge; Looso, Mario; Günther, Stefan; Wanke, Florian; Moos, Sonja; Siller, Nelly; Breuer, Johanna; Schwab, Nicholas; Zipp, Frauke; Waisman, Ari; Kurschus, Florian C.; Offermanns, Stefan; Wettschureck, Nina

doi:10.1172/jci.insight.95063

Cited by 21 publications

(14 citation statements)

References 73 publications

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“…4e). Cluster 2-4 0 corresponded to activated cytokine-secreting IL23R + T H 17, whereas cluster 2-4 1 expressed CXCR4, GPR183, and CXCR3, which indicate quiescent T H 17 33 (Fig. 4f and Supplementary Fig.…”

Section: Iel Show An Aberrant Representation Of T Cell Subsets In CDmentioning

confidence: 99%

Single-cell analyses of Crohn’s disease tissues reveal intestinal intraepithelial T cells heterogeneity and altered subset distributions

et al. 2021

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Crohn’s disease (CD) is a chronic transmural inflammation of intestinal segments caused by dysregulated interaction between microbiome and gut immune system. Here, we profile, via multiple single-cell technologies, T cells purified from the intestinal epithelium and lamina propria (LP) from terminal ileum resections of adult severe CD cases. We find that intraepithelial lymphocytes (IEL) contain several unique T cell subsets, including NKp30+γδT cells expressing RORγt and producing IL-26 upon NKp30 engagement. Further analyses comparing tissues from non-inflamed and inflamed regions of patients with CD versus healthy controls show increased activated TH17 but decreased CD8+T, γδT, TFH and Treg cells in inflamed tissues. Similar analyses of LP find increased CD8+, as well as reduced CD4+T cells with an elevated TH17 over Treg/TFH ratio. Our analyses of CD tissues thus suggest a potential link, pending additional validations, between transmural inflammation, reduced IEL γδT cells and altered spatial distribution of IEL and LP T cell subsets.

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Section: Iel Show An Aberrant Representation Of T Cell Subsets In CDmentioning

confidence: 99%

Single-cell analyses of Crohn’s disease tissues reveal intestinal intraepithelial T cells heterogeneity and altered subset distributions

et al. 2021

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“…Single-cell RNA sequencing data revealed that almost every cell type investigated expresses dozens of different GPCRs, with some sharing similar signaling properties (Kaur et al, 2017;Tischner et al, 2017). It is therefore reasonable to stimulate endogenously coexpressed GPCRs to restore signaling of the mutant receptor (Fig.…”

Section: A Symptomatic Therapies Of Gpcr Pathologiesmentioning

confidence: 99%

Mutations in G Protein–Coupled Receptors: Mechanisms, Pathophysiology and Potential Therapeutic Approaches

Schöneberg¹,

Liebscher²

2020

Pharmacol Rev

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There are approximately 800 annotated G protein-coupled receptor (GPCR) genes, making these membrane receptors members of the most abundant gene family in the human genome. Besides being involved in manifold physiologic functions and serving as important pharmacotherapeutic targets, mutations in 55 GPCR genes cause about 66 inherited monogenic diseases in humans. Alterations of nine GPCR genes are causatively involved in inherited digenic diseases. In addition to classic gain-and loss-of-function variants, other aspects, such as biased signaling, trans-signaling, ectopic expression, allele variants of GPCRs, pseudogenes, gene fusion, and gene dosage, contribute to the repertoire of GPCR dysfunctions. However, the spectrum of alterations and GPCR involvement is probably much larger because an additional 91 GPCR genes contain homozygous or hemizygous loss-of-function mutations in human individuals with currently unidentified phenotypes. This review highlights the complexity of genomic alteration of GPCR genes as well as their functional consequences and discusses derived therapeutic approaches. Significance Statement-With the advent of new transgenic and sequencing technologies, the number of monogenic diseases related to G protein-coupled receptor (GPCR) mutants has significantly increased, and our understanding of the functional impact of certain kinds of mutations has substantially improved. Besides the classical gain-and loss-of-function alterations, additional aspects, such as biased signaling, trans-signaling, ectopic expression, allele variants of GPCRs, uniparental disomy, pseudogenes, gene fusion, and gene dosage, need to be elaborated in light of GPCR dysfunctions and possible therapeutic strategies.

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“…Most studies to date have assessed tissues or mixed populations of cells. However, recent evidence, especially from assessment of mRNA expression in single cells, i.e., single cell gene expression, indicates that sub-populations of cells differentially express many mRNAs, including GPCRs with different expression profiles and magnitude of expression, including in individual neurons [54,55], vascular and immune cells [56,57) and with cell-specific changes in disease models. Such studies typically isolate single cells using microfluidic techniques.…”

Section: Limitations Of Current Gpcromic Approachesmentioning

confidence: 99%

GPCRomics: An Approach to Discover GPCR Drug Targets

Insel

Sriram

Gorr

et al. 2019

Trends in Pharmacological Sciences

139

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G protein-coupled receptors (GPCRs) are targets for ~35% of approved drugs but only ~15% of the ~800 human GPCRs are currently such targets. GPCRomics, the use of unbiased, hypothesisgenerating methods (e.g., RNA-sequencing [RNA-seq]), with tissues and cell types to identify and quantify GPCR expression, has led to the discovery of previously unrecognized GPCRs that contribute to functional responses and pathophysiology and that may be therapeutic targets. The combination of GPCR expression data with validation studies (e.g., signaling and functional activities) provides opportunities for the discovery of disease-relevant GPCR targets and therapeutics. Here, we review insights from GPCRomic approaches, gaps in knowledge and future directions by which GPCRomics can advance GPCR biology and the discovery of new GPCRtargeted drugs.

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Single-cell profiling reveals GPCR heterogeneity and functional patterning during neuroinflammation

Cited by 21 publications

References 73 publications

Single-cell analyses of Crohn’s disease tissues reveal intestinal intraepithelial T cells heterogeneity and altered subset distributions

Single-cell analyses of Crohn’s disease tissues reveal intestinal intraepithelial T cells heterogeneity and altered subset distributions

Mutations in G Protein–Coupled Receptors: Mechanisms, Pathophysiology and Potential Therapeutic Approaches

GPCRomics: An Approach to Discover GPCR Drug Targets

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