The GABA and GABA-Receptor System in Inflammation, Anti-Tumor Immune Responses, and COVID-19

Abstract

GABA and GABAA-receptors (GABAA-Rs) play major roles in neurodevelopment and neurotransmission in the central nervous system (CNS). There has been a growing appreciation that GABAA-Rs are also present on most immune cells. Studies in the fields of autoimmune disease, cancer, parasitology, and virology have observed that GABA-R ligands have anti-inflammatory actions on T cells and antigen-presenting cells (APCs), while also enhancing regulatory T cell (Treg) responses and shifting APCs toward anti-inflammatory phenotypes. These actions have enabled GABAA-R ligands to ameliorate autoimmune diseases, such as type 1 diabetes (T1D), multiple sclerosis (MS), and rheumatoid arthritis, as well as type 2 diabetes (T2D)-associated inflammation in preclinical models. Conversely, antagonism of GABAA-R activity promotes the pro-inflammatory responses of T cells and APCs, enhancing anti-tumor responses and reducing tumor burden in models of solid tumors. Lung epithelial cells also express GABA-Rs, whose activation helps maintain fluid homeostasis and promote recovery from injury. The ability of GABAA-R agonists to limit both excessive immune responses and lung epithelial cell injury may underlie recent findings that GABAA-R agonists reduce the severity of disease in mice infected with highly lethal coronaviruses (SARS-CoV-2 and MHV-1). These observations suggest that GABAA-R agonists may provide off-the-shelf therapies for COVID-19 caused by new SARS-CoV-2 variants, as well as novel beta-coronaviruses, which evade vaccine-induced immune responses and antiviral medications. We review these findings and further advance the notions that (1) immune cells possess GABAA-Rs to limit inflammation in the CNS, and (2) this natural “braking system” on inflammatory responses may be pharmacologically engaged to slow the progression of autoimmune diseases, reduce the severity of COVID-19, and perhaps limit neuroinflammation associated with long COVID.

Serum Metabolomics of Retinoblastoma: Assessing the Differential Serum Metabolic Signatures of Unilateral and Bilateral Patients

“…Rb cells utilize either all of these biosynthetic pathways or use one of them selectively for the GABA synthesis . Studies have depicted an aberrant expression of GAD in different cancers which reorients the glutamine metabolism toward the GABA synthesis and thereby results in secretion of GABA. , Secreted forms of GABA play vital roles in (1) activating GABA receptors present on tumor cells, thereby facilitating the inactivation of GSK-3β which in turn results in increased β-catenin signaling and tumor growth, and (2) blocking the infiltration of CD8+ T-cells in tumor . It is noteworthy that β-catenin activation is positively correlated to Rb progression and survival.…”

GABA, glucose and insulin orchestrate CD4+T cells effector functions

“…The freshly isolated CD4 + T cells (1x 10 6 /ml) were suspended in RPMI 1640 glucose-free medium (Gibco, Fisher Scientific, Sweden) supplemented with 2 mM glutamine, 10% heat-inactivated dialyzed fetal bovine serum, 100 U/ml penicillin, 10 mg/ml streptomycin, and 5 μM β-mercaptoethanol (Gibco, Fisher Scientific, Sweden). The activation of the cells was performed in either 96-well (10 5 cell/well) or 24-well (10 6 cell/well) plates based on the purpose of the experiment. CD4 + T cells were activated with 3 μg/ml plate-bound anti-CD3 (BD Biosciences, USA, 555329) in the presence of different concentrations of glucose (2.8 mM, 5.6 mM, 10 mM and 16.7 mM) for 66 _ 72 h and indicated drugs were added based on the experimental design.…”

“…The cells were kept in XF media (Seahorse Bioscience) supplemented with 5 mM glucose (Sigma Aldrich), and subjected to glycolysis stress-test protocol using sequential injection of 25 mM glucose, 2 μM oligomycin, and finally 15 mM 2-deoxyglucose (2DG). Measurements for each experiment were conducted at least in triplicates and glycolysis, glycolytic capacity, and glycolytic reserve calculated and values normalized to protein content 4, 5 .…”

“…The cells were kept in XF media (Seahorse Bioscience) supplemented with 5 mM glucose (Sigma Aldrich), and subjected to glycolysis stress-test protocol using sequential injection of 25 mM glucose, 2 μM oligomycin, and finally 15 mM 2-deoxyglucose (2DG). Measurements for each experiment were conducted at least in triplicates and glycolysis, glycolytic capacity, and glycolytic reserve calculated and values normalized to protein content 4,5 . Glucose uptake assay 2x 10 6 activated CD4 + T cells (72 h activation) with insulin treatment from 48 h after activation were pelleted, resuspended in glucose-free RPMI-1640 media, incubated for 10 min in the incubator at 37 °C, and washed once with the same media.…”

“…A variety of soluble molecules including amino acids, other nutrients and hormones that are present in blood, lymph nodes and tissue microenvironment influence T cell function [2][3][4] . γ-aminobutyric acid (GABA), is primarily known as an inhibitory neurotransmitter in the central nervous system, but is increasingly recognized as an immunomodulatory molecule [5][6][7] . We and others have previously shown that GABA inhibits proliferation and cytokine secretion by activating GABAA receptors in CD4 + T cells [8][9][10] .…”