GABA_Areceptor α₄-subunit knockout enhances lung inflammation and airway reactivity in a murine asthma model

Abstract

Emerging evidence indicates that hypnotic anesthetics affect immune function. Many anesthetics potentiate γ-aminobutyric acid A receptor (GABAR) activation, and these receptors are expressed on multiple subtypes of immune cells, providing a potential mechanistic link. Like immune cells, airway smooth muscle (ASM) cells also express GABARs, particularly isoforms containing α-subunits, and activation of these receptors leads to ASM relaxation. We sought to determine if GABAR signaling modulates the ASM contractile and inflammatory phenotype of a murine allergic asthma model utilizing GABAR α-subunit global knockout (KO; ) mice. Wild-type (WT) and KO mice were sensitized with house dust mite (HDM) antigen or exposed to PBS intranasally 5 days/wk for 3 wk. Ex vivo tracheal rings from HDM-sensitized WT and KO mice exhibited similar magnitudes of acetylcholine-induced contractile force and isoproterenol-induced relaxation ( = not significant; = 4). In contrast, in vivo airway resistance (flexiVent) was significantly increased in KO mice ( < 0.05, = 8). Moreover, the KO mice demonstrated increased eosinophilic lung infiltration ( < 0.05; = 4) and increased markers of lung T-cell activation/memory (CD62L low, CD44 high; < 0.01, = 4). In vitro, KO CD4 cells produced increased cytokines and exhibited increased proliferation after stimulation of the T-cell receptor as compared with WT CD4 cells. These data suggest that the GABAR α-subunit plays a role in immune cell function during allergic lung sensitization. Thus GABAR α-subunit-specific agonists have the therapeutic potential to treat asthma via two mechanisms: direct ASM relaxation and inhibition of airway inflammation.

Slc6a13 deficiency promotes Th17 responses during intestinal bacterial infection

“…2 Likewise, results from other investigations also support the conclusion that GABAergic system inhibits the immune responses. [3][4][5] However, GABA promotes intestinal Th17 cell differentiation and interleukin-17 (IL-17) expression during enterotoxigenic Escherichia coli (ETEC) infection in piglets and mice. 6 Thus, the effect of the GABAergic system in the immune system needs further investigations.…”

GABAA Receptor Subtypes Regulate Stress-Induced Colon Inflammation in Mice

“…[37][38][39] GABA A Rs have now been shown to have an important role in peripheral inflammatory disorders such as asthma. 40,41 It is therefore surprising that the role of GABA A Rs in major peripheral inflammatory disorders such as IBD is poorly understood, even though preliminary evidence suggests that some GABA A R ligands could prove therapeutically useful for such conditions. 13 The current study provides proof of concept that a3-GABA A Rs, in particular, play a direct role in mediating stress-induced GI inflammation, because the constitutive deletion of the GABA A R a3 subunit gene abolished stress-induced colonic inflammation (Figure 4).…”

“…These data are closely aligned with previous reports of an anti-inflammatory role for a4-GABA A Rs in other organs such as lung. 40 This positions various GABA A R subtypes as dynamic regulators of the local GI immune system, capable of maintaining the balance of inflammation, and therefore as potential targets for treating IBD. The targeting of GI GABA A Rs could provide new opportunities for GABA A R compounds that have been discarded because of their inability to penetrate the central nervous system and repurposing of clinically available ligands for such peripheral disorders.…”

“…9,10 Emerging evidence now points to various GABA A R subtypes directly associated with neuroinflammation within the brain 11 and inflammatory disorders in peripheral organs, such as asthma. 12 Furthermore, the anti-epileptic drug topiramate, which has GABA A R agonist properties, has been shown to ameliorate the macroscopic and microscopic GI inflammation score in an animal model of IBD. 13 Despite this convincing evidence for a role of GABA A Rs in contributing to stress and inflammatory responses, their roles in IBD are relatively poorly understood, primarily because of our limited understanding of GABA A R function in the GI immune system.…”

Molecular Characterization of GABA-A Receptor Subunit Diversity within Major Peripheral Organs and Their Plasticity in Response to Early Life Psychosocial Stress

“…Emerging evidence indicates the widespread effects of GABA A Rs on the native functioning and pathologies of various organs. For example, GABA A Rs have been shown to have a pronounced effect on various facets of lung function, ranging from inflammation ( Yocum et al, 2017 ), asthma ( Forkuo et al, 2017 ), lung cancer ( Liu et al, 2016 ) to airway smooth muscle contractility ( Gallos et al, 2015 ). However, within other peripheral organs such as kidney, relatively less is known about the role of GABA–GABA A R system.…”