Diminished antigen-specific IgG1 and interleukin-6 production and acetylcholinesterase expression in combined M1 and M5 muscarinic acetylcholine receptor knockout mice

Fujii, Yoshihito X.; Tashiro, Akari; Arimoto, Kumiko; Fujigaya, Hirofumi; Moriwaki, Yuji; Misawa, Hidemi; Fujii, Takeshi; Matsui, Masanao; Kimura, Tadashi; Kawashima, Koichiro

doi:10.1016/j.jneuroim.2007.05.017

Cited by 52 publications

(38 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…19 However, in the combined M 1 and M 5 mAChR knockout mice, there is no significant change in IFN-c secretion, but there is decreased IL-6 production. 20 This is in accordance with our demonstration that SCP does not affect Th1 response. Since IL-6 is a critical differentiation factor for the generation of Th17 cells, 26 the downregulated Th17 response by SCP administration may be due to the decreased expression of IL-6.…”

Section: Discussionsupporting

confidence: 92%

“…15 The activation of mAChRs has been shown to enhance intracellular Ca 2þ signaling and upregulate c-fos mRNA expression, 16 increase phytohemagglutinin-induced IL-2 production, 17 enhance T-cell proliferation, 18 and decrease IFN-c synthesis. 19 Conversely, inhibition of mAChRs decreases IL-6 secretion 20 and suppresses leukocytic infiltration. 18 To date, to our knowledge the role of mAChRs on each individual CD4 þ T-cell subset in vivo has yet to be determined.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Effect of Desiccating Environmental Stress Versus Systemic Muscarinic AChR Blockade on Dry Eye Immunopathogenesis

Chen

Chauhan

Lee

et al. 2013

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

PURPOSE. A majority of experimental data on dry eye disease (DED) immunopathogenesis have been derived from a murine model of DED that combines desiccating environmental stress with systemic muscarinic acetylcholine receptor (mAChR) inhibition. However, to our knowledge the effects of pharmacologic mAChR blockade on the pathogenesis of experimental DED have not been evaluated systemically. The purpose of our study was to investigate the differential effects of desiccating environmental stress and mAChR inhibition on the pathogenesis of DED.METHODS. DED was induced in female C57BL/6 mice by exposure to a desiccating environment in the controlled-environment chamber or to systemic scopolamine, or by performing extraorbital lacrimal gland excision. Clinical disease was assessed using corneal fluorescein staining (CFS) and the cotton thread test (CTT). Corneal CD11b þ and conjunctival CD3 þ T-cell infiltration were evaluated by flow cytometry. T-cells from draining cervical lymph nodes (CLN) and distant inguinal lymph nodes (ILN) were analyzed for Th1, Th2, Th17, and Treg responses by flow cytometry and ELISA.RESULTS. Desiccating environmental stress and systemic mAChR blockade induced similar clinical signs of DED. However, desiccating environmental stress imparted higher conjunctival CD3 þ T-cell infiltration, and greater Th17-cell activity and Treg dysfunction than mAChR blockade, while mAChR blockade decreased tear secretion to a greater extent than desiccating environmental stress. Systemic mAChR blockade attenuated Th17 activity and enhanced Th2 and Treg responses without affecting Th1 activity. CONCLUSIONS. In vivo inhibition of mAChRs variably affects CD4þ T-cell subsets, and desiccating environmental stress and systemic mAChR blockade induce DED through different primary pathogenic mechanisms.

show abstract

Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Effect of Desiccating Environmental Stress Versus Systemic Muscarinic AChR Blockade on Dry Eye Immunopathogenesis

Chen

Chauhan

Lee

et al. 2013

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

show abstract

“…23 In marked contrast, immunized M 1 /M 5 mAChR knockout mice show diminished antigen-specific IgG 1 production. 24 The reported pro-inflammatory/immunostimulatory effects of nicotine include increased secretion of IL-12 by Th1 T cells, 25 enhanced Con A-induced production of IFN-g 26 and protection of lymphocytes from cortisol-induced apoptosis. 27 It has been proposed that the nicotinergic pro-inflammatory cascade is mediated by a9 nAChR.…”

Section: Discussionmentioning

confidence: 99%

Plasticity of the murine spleen T-cell cholinergic receptors and their role in in vitro differentiation of naïve CD4 T cells toward the Th1, Th2 and Th17 lineages

et al. 2011

View full text Add to dashboard Cite

Acetylcholine (ACh) regulates vital functions of T cells by acting on the nicotinic and muscarinic classes of cholinergic receptors, nAChR and mAChRs, respectively. This study was performed in murine splenic T cells. In freshly isolated CD4 and CD8 T cells, we detected mRNAs encoding a5, a9, a10, b1, b2, b4 nAChR subunits and M 1 , M 3 , M 4 and M 5 mAChR subtypes, whereas a2 was detected only in CD8 T cells. In vitro activation of CD4 T cells through T-cell receptor (TCR)/CD3 cross-linking was associated with the appearance of a4 and a7, upregulation of a5, a10, b4, M 1 and M 5 and downregulation of a9 and b2, whereas in vitro activation of CD8 T cells also featured the appearance of a4 and a7, as well as upregulation of a2, a5, b4, M 1 and M 4 , and downregulation of a10, b1, b2 and M 3 . In vitro polarization toward T helper (Th) 1 lineage was associated with a decrease of b2, b4 and M 3 expression; that toward Th2 cells with downregulation of a9 and M 3 , and upregulation of M 1 and M 5 ; and that toward Th17 phenotype with downregulation of a9, a10, b2 and M 3 mAChR. Polarized T cells also expressed a4, but not a1, a2, a3, a6, b3 or M 2 . To determine the role of cholinergic receptors in mediating the immunoregulatory action of autocrine/paracrine ACh, we analyzed the effects of nicotinic and muscarinic agonists ± antagonists on cytokine production in the CD4 þ CD62L þ T cells co-stimulated via TCR/CD3 cross-linking. The nicotinergic stimulation upregulated interferon-g (IFN-g) and downregulated interleukin (IL)-17 secretion, whereas the muscarinic stimulation enhanced IL-10 and IL-17 and inhibited INF-g secretion. These results demonstrated plasticity of the T-cell cholinergic system.

show abstract

“…Numerous studies revealed that mAChR activation has pro-inflammatory effects in different cell types. Accordingly, activated mononuclear leucocytes from M1/M5 mAChR-deficient mice produced significantly less pro-inflammatory cytokines [173]. Further, mAChR stimulation increases the number of leucocytes in splenic venous blood [174].…”

Section: Immune Systemmentioning

confidence: 99%

The Non-Neuronal Cholinergic System in Health and Disease

Beckmann¹,

Lips²

2013

Pharmacology

100

View full text Add to dashboard Cite

Acetylcholine (ACh) is not only a neurotransmitter but is an ancient molecule that can be released by and act on non-neuronal cells. In these cells the system of ACh-synthesizing enzymes, transporters, receptors and degrading enzymes is termed the non-neuronal cholinergic system (NNCS). There is increasing evidence that the NNCS is dysregulated in various diseases and can have an influence on their pathology. However, for many organ systems not much is known about the expression and function of the NNCS. Thus, this review focusses on the role of the NNCS in different organ systems in health and disease. Dysregulation of ACh synthesis and release, mutations or polymorphisms in genes encoding NNCS components, and auto-antibodies against NNCS components are common factors influencing disease progression. Pharmacological agents targeting the NNCS are already successfully in clinical use for some disorders, indicating that interfering with this system is very promising and more research is needed to elucidate the role of the NNCS in different tissues and pathological states.

show abstract

Diminished antigen-specific IgG1 and interleukin-6 production and acetylcholinesterase expression in combined M1 and M5 muscarinic acetylcholine receptor knockout mice

Cited by 52 publications

References 30 publications

Effect of Desiccating Environmental Stress Versus Systemic Muscarinic AChR Blockade on Dry Eye Immunopathogenesis

Effect of Desiccating Environmental Stress Versus Systemic Muscarinic AChR Blockade on Dry Eye Immunopathogenesis

Plasticity of the murine spleen T-cell cholinergic receptors and their role in in vitro differentiation of naïve CD4 T cells toward the Th1, Th2 and Th17 lineages

The Non-Neuronal Cholinergic System in Health and Disease

Contact Info

Product

Resources

About