Identification of M3 muscarinic acetylcholine receptor reactive Th17 cells in patients with primary Sjögren’s syndrome
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA626633 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11575703.fastq.gz | Fastqsanger.gz | |||
| SRR11575704.fastq.gz | Fastqsanger.gz | |||
| SRR11575705.fastq.gz | Fastqsanger.gz |
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Project description:Previously M3 muscarinic acetylcholine receptore (M3R) reactive Th1 cells were identified, and here, M3R reactive Th17 cells were identified in peripheral blood of primary Sjögren’s syndrome patients using ELISpot method. To assess TCR repertoire overlap between identified M3R reactive Th17 cells, and salivary gland infiltrating T cells, we performed high throughput TCR sequencing of those cells from pSS patient.
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Project description:The M3 muscarinic acetylcholine receptor (CHRM3) is predominantly expressed in the basal epidermal layer where it mediates the effects of the auto/paracrine cytotransmitter acetylcholine. Patients with the autoimmune blistering disease pemphigus develop autoantibodies to CHRM3 and show alterations in keratinocyte adhesion, proliferation and differentiation, suggesting that CHRM3 controls these cellular functions. Chrm3 mice display altered epidermal morphology resembling that seen in patients with pemphigus vulgaris. Here, we characterized the cellular and molecular mechanisms whereby CHRM3 controls epidermal structure and function. We used single cell (sc)RNA-seq to evaluate keratinocyte heterogeneity and identify differentially expressed genes in specific subpopulations of epidermal cells in Chrm3 KO neonatal mice.
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Project description:Muscarinic acetylcholine receptor M3 (M3) and its downstream effector Gq/11 are critical drug development targets given their involvement in numerous physiological processes and diseases. Although a cryo-electron microscopy study previously defined the structure of the M3-miniGq complex, the lack of information on the intracellular loop 3 (ICL3) of M3 and α-helical domain (AHD) of Gαq has made it difficult to comprehend the molecular mechanism of M3-Gq coupling fully. Here, we present the molecular mechanism underlying the dynamic interactions between the wild-type full-length M3 and heterotrimeric Gq using hydrogen-deuterium exchange mass spectrometry and NanoLuc Binary Technology-based cell systems. This study suggests potential binding interfaces between M3 and Gq in pre-assembled and fully active nucleotide-free complexes. In addition to well-known binding interfaces, we observed the interaction of long ICL3 with Gβγ. Furthermore, M3 ICL3 negatively affected M3-Gq coupling, and the Gαq AHD underwent unique conformational changes during M3-Gq coupling. Therefore, we propose a comprehensive molecular mechanism of M3-Gq coupling by analyzing previously well-defined binding interfaces and neglected regions, such as M3 ICL3 and the Gαq AHD.
2024-05-22 | PXD042562 | Pride
Project description:The M3 Muscarinic Acetylcholine Receptor Promotes Epidermal Differentiation
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Project description:The muscarinic acetylcholine receptor 4 was inducibly deleted in Math1 expressing lineages and alterations in gene expression evaluated by bulk RNA sequencing
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Project description:M3 muscarinic acetylcholine receptor (M3R) is one of the autoantigens associated with Sjögren's syndrome (SS) and is localized in exocrine glands where disease-specific inflammation occurs. The inflammatory lesion is characterized by infiltration of CD4+ T cells, including clonally expanded Th17 cells. We undertook this study to identify circulating M3R-specific Th17 cells and to determine functional properties of those cells. Using the enzyme-linked immunospot assay (ELISpot) method, we identified M3R-reactive Th17 cells in the peripheral blood of patients with primary SS (pSS). Among 10 examined pSS patients, 10 healthy subjects (HS), and 5 IgG4-related disease (IgG4-RD) patients, M3R-reactive IL-17 secreting cells were significantly increased in 5 pSS patients specifically. The most common T cell epitope, which was analyzed and confirmed by coculture of isolated CD4+ T cells with antigen presenting cells plus M3R peptides in vitro, was peptide 83-95 of M3R. Peptide recognition was partly in an HLA-DR-restricted manner, confirmed by blocking assay. M3R-reactive Th17 cells positivity correlated with higher titers of anti-M3R antibodies, whose systemic disease activity score tended to be higher. Our studies highlight the role of tissue-specific autoantigen-derived circulating Th17 cells in pSS, for which further work might lead to antigen-specific targeted therapy.
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Project description:The long blood feeding duration of hard ticks relies on the continuous modulation of saliva composition to manipulate host haemostatic and immune systems. While the exogenous muscarinic acetylcholine receptor (mAChR) agonist, pilocarpine, is a potent inducer of tick salivation, the underlying control mechanisms of endogenous stimulation remain unclear. Here, we characterised two pharmacologically distinct types of mAChRs (A and B) in the genome of the Ixodes ricinus tick. A combination of molecular dynamics and directed mutagenesis revealed the atypical muscarinic profile of the type-B receptor. Immunolabelling followed by in vivo pharmacology and proteomic analyses suggested that the composition of secreted saliva is a result of a complex interplay between different central neurons and specific regions of the salivary gland (SG), mediated by distinct axonal mAChR types. This system likely functions upstream of a neuropeptide signalling cascade, ultimately controlling different salivation subunits in SG. Our study describes a unique model of regulation of tick SG activity in a medically relevant tick species. This knowledge holds broader implications for understanding tick-host interactions.
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Project description:In contrast to most peripheral tissues where multiple subtypes of muscarinic acetylcholine receptor (mAChR) coexist, with each of them playing its part in the orchestra of parasympathetic innervation, the myocardium has been traditionally considered to possess a single mAChR subtype. Although there is much evidence to support the notion that one receptor subtype (M2) orchestrates myocardial muscarinic transduction, there is emerging evidence that M1 and M3 receptors are also expressed and are of potential physiological, pathophysiological and pharmacological relevance. Clarifying this issue has a profound impact on our thinking about the cholinergic control of the heart function and disease and approaches to new drug development for the treatment of heart disease associated with parasympathetic dysfunction. This review article presents evidence for the presence of the M3 receptor subtype in the heart, and analyzes the controversial data from published pharmacological, functional and molecular studies. The potential roles of the M3 receptors, in parasympathetic control of heart function under normal physiological conditions and in heart failure, myocardial ischemia and arrhythmias, are discussed. On the basis of these considerations, we have made some proposals concerning the future of myocardial M3 receptor research.
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Project description:The M3 muscarinic acetylcholine receptor is predominantly expressed in the basal epidermal layer where it mediates the effects of the autocrine/paracrine cytotransmitter acetylcholine. Patients with the autoimmune blistering disease pemphigus develop autoantibodies to M3 muscarinic acetylcholine receptor and show alterations in keratinocyte adhesion, proliferation, and differentiation, suggesting that M3 muscarinic acetylcholine receptor controls these cellular functions. Chmr3-/- mice display altered epidermal morphology resembling that seen in patients with pemphigus vulgaris. In this study, we characterized the cellular and molecular mechanisms through which M3 muscarinic acetylcholine receptor controls epidermal structure and function. We used single-cell RNA sequencing to evaluate keratinocyte heterogeneity and identify differentially expressed genes in specific subpopulations of epidermal cells in Chmr3-/- neonatal mice. We found that Chmr3-/- mice feature abnormal epidermal morphology characterized by accumulation of nucleated basal cells, shrinkage of basal keratinocytes, and enlargement of intercellular spaces. These morphologic changes were associated with upregulation of cell proliferation genes and downregulation of genes contributing to epidermal differentiation, extracellular matrix formation, intercellular adhesion, and cell arrangement. These findings provide, to our knowledge, previously unreported insights into how acetylcholine controls epidermal differentiation and lay a groundwork for future translational studies evaluating the therapeutic potential of cholinergic drugs in dermatology.
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Project description:Antimuscarinic drugs such as pirenzepine (PZ) and muscarinic toxin 7 (MT7), long considered M1 muscarinic acetylcholine receptor (M1R) antagonists, exhibit beta-arrestin-biased agonism. Using HEK293 cells and adult dorsal root ganglion (DRG) neurons, we show that PZ and MT7 selectively recruit beta-arrestin to M1R, activate ERK1/2 signaling, and promote neurite outgrowth without engaging G-alpha-q pathways or receptor internalization. Mass spectrometry identified six key M1R phosphorylation sites (T230, S251, T254, S321, T354, S356) required for beta-arrestin recruitment, with S251/T254 essential for PZ signaling. Casein kinase 2 (CK2), but not GRKs, mediates this phosphorylation; CK2 inhibition blocks beta-arrestin binding, ERK activation, and neurite outgrowth. These findings redefine antimuscarinic drugs as partial, beta-arrestin-biased M1R agonists and identify CK2 as a critical modulator of non-canonical M1R signaling relevant to sensory neuron regeneration and neuropathy therapy.
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