GABA regulates release of inflammatory cytokines from peripheral blood mononuclear cells and CD4+ T cells and is immunosuppressive in type 1 diabetes
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ABSTRACT:
PROVIDER: PRJNA438490 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR6841730.fastq.gz | Fastqsanger.gz | |||
| SRR6841740.fastq.gz | Fastqsanger.gz | |||
| SRR6841750.fastq.gz | Fastqsanger.gz | |||
| SRR6841760.fastq.gz | Fastqsanger.gz | |||
| SRR6841770.fastq.gz | Fastqsanger.gz |
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Project description:The neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule in the brain and in pancreatic islets. Here, we demonstrate that GABA regulates cytokine secretion from human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells. In anti-CD3 stimulated PBMCs, GABA (100nM) inhibited release of 47 cytokines in cells from patients with type 1 diabetes (T1D), but only 16 cytokines in cells from nondiabetic (ND) individuals. CD4+ T cells from ND individuals were grouped into responder or non-responder T cells according to effects of GABA (100nM, 500nM) on the cell proliferation. In the responder T cells, GABA decreased proliferation, and inhibited secretion of 37 cytokines in a concentration-dependent manner. In the non-responder T cells, GABA modulated release of 8 cytokines. GABA concentrations in plasma from T1D patients and ND individuals were correlated with 10 cytokines where 7 were increased in plasma of T1D patients. GABA inhibited secretion of 5 of these cytokines from both T1D PBMCs and ND responder T cells. The results identify GABA as a potent regulator of both Th1- and Th2-type cytokine secretion from human PBMCs and CD4+ T cells where GABA generally decreases the secretion.
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Project description:This study compared the transcriptome profiling (RNA-seq) of CD3+ T cells from nondiabetic (ND) individuals and patients with type 1 diabetes (T1D).
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Project description:Metabolic programs of immune cells are closely linked to their effector functions , where physiological molecules provide environmental cues and guidance. Exactly how it happens is still being unraveled. Insulin maintains normal blood glucose levels and glucose is themain source of energy and a precursor for many biomolecules in T cells, whereas γ-aminobutyric acid (GABA), best known as a neurotransmitter, is increasingly recognized as a regulatory molecule in the immune system. Here, we demonstrate that GABA-mediated reduction of metabolic activity and release of inflammatory molecules, including IFNγ and IL-10, was abolished in human CD4+ T cells, when the glucose concentration was elevated above normal levels. In a glucose concentration-dependent manner, insulin enhanced the GABAA receptors activated currents and GABA-dependent Ca2+ influx. GABA decreased, whereas insulin maintained glycolysis but in a SGLT (Na + -glucose transporter)-dependent manner, revealing expression of SGLTs in activated CD4+ T cells. The SGLTs antagonist phlorizin, alone or together with GABA, restored the inhibition of IFNγ and IL-10 release in presence of high glucose. This study exposes concerted effects of GABA, glucose and insulin on CD4+ T cells metabolic activity and release of inflammatory molecules, and identifies a role for SGLTs in CD4+ T cells function.
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Project description:Small, soluble metabolites are not only essential intermediates in intracellular biochemical processes, but can also influence neighboring cells when released into the extracellular milieu. Here, we identify the metabolite and neurotransmitter GABA as a candidate signaling molecule synthesized and secreted by activated B cells and plasma cells. We show that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages which secrete IL-10 and inhibit CD8+ T cell killer function. In mice, B cell deficiency or B cell-specific inactivation of the GABA generating enzyme GAD67 enhances anti-tumor responses. Our study reveals that in addition to cytokines and membrane proteins, small metabolites derived from B lineage cells have immunoregulatory functions, which may be pharmaceutical targets allowing fine-tuning of immune responses.
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Project description:Neurotransmitters have been well-documented to determine immune cell fates; however, whether and how γ-amino butyric acid (GABA) shapes the function of innate immune cells is still obscure. Here, we demonstrated that GABA orchestrates macrophage maturation and inflammation. GABA treatment during macrophage maturation inhibits interleukin (IL)-1β production from inflammatory macrophages. Mechanistically, GABA enhances succinate-FAD-lysine demethylase1 (LSD1) signaling to regulate the histone demethylation of Bcl2l11 and Dusp2, lowering the formation of NLRP3-ASC-Caspase-1 complex. Meanwhile, GABA-succinate axis lowers succinylation of mitochondrial proteins to promote mitochondrial oxidative phosphorylation (OXPHOS). We also found that GABA alleviates the LPS-induced sepsis as well as high-fat diet-induced obesity in mice. Our study proves that GABA is potential in lessening the pro-inflammatory macrophage responses associating with metabolic reprogramming and protein succinylation, thus providing a strategy for treating macrophage-related inflammatory diseases.
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Project description:Hepatic lipid accumulation is a hallmark of type 2 diabetes (T2D) and associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and also knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia, and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from obese humans support that hepatic GABA production and transport are associated with serum insulin, HOMA-IR, T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity.
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Project description:Neuropeptide Y (NPY) is an endogenous modulator of neuronal activity by regulating GABA and glutamate release. Previously, we found that estradiol modulates NPY expression in the hippocampal dentate gyrus. Here we investigated which estrogen receptor type activation is required for the NPY expression. Further, we determined effects of estrogen receptor activation on NPY release. Finally, we determined the contribution of estrogen-mediated remodeling of the GABAergic and glutamatergic network in relation to changes in coupling with NPY in ovariectomized rats. We found that activation of either estrogen receptor type increases NPY expression as well as NPY release in the dentate gyrus. We also found that compared to OVX rats, estrogen replacement increases the likeness of synergistic/antagonistic coupling between the NPY and GABAergic synapse genes while the glutamatergic synapse genes are less likely coupled with NPY. The data together suggest that estrogen plays a critical role in regulation of activity of the NPY system and its coupling to GABAergic and glutamatergic synapses in female rat dentate gyrus. Two-conditions (E = beta-estradiol replacement vs O = oil) experiment. Biological replicates: 4E, 4O.
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Project description:au05-03_gaba - ler vs pop2-1: gaba over-accumulation effects - The analysis aims at identifying genes that are differentially regulated by the over-accumulation of GABA observed in the mutant pop2-1 in response to treatment with exogenous GABA and that may explain the singular phenotype of the mutant in this condition. Designed experiment consisted in comparison of transcriptomes of Arabidopsis thaliana Landsberg erecta ecotype and its mutant pop2-1 (impaired in GABA transaminase activity) during a kinetic of endogenous GABA accumulation. For this purpose, 10-day-old plants grown on half strength Hoagland's agar medium were transferred to agar plates supplemented with 1 mM GABA. We isolated RNA from plants treated for 0, 1 and 4 days. Treatments were made in duplicate. Keywords: gene knock-out, time course 6 dye-swap - CATMA arrays
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