GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections

Jin Kyung Kim,Yi Sak Kim,Jung-Joon Min,Jin-Man Kim,Hyon E Choy,Masahiro Yamamoto,Jin Bong Park,Sang-Hee Lee,Hyo Sun Jin,Chiranjivi Neupane,Hye-Mi Lee,Jae-Ho Jeong,Miwa Sasai,Eun-Kyeong Jo,Sup Kim,Seong-Kyu Choe

doi:10.1038/s41467-018-06487-5

Abstract

Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain; however, the roles of GABA in antimicrobial host defenses are largely unknown. Here we demonstrate that GABAergic activation enhances antimicrobial responses against intracellular bacterial infection. Intracellular bacterial infection decreases GABA levels in vitro in macrophages and in vivo in sera. Treatment of macrophages with GABA or GABAergic drugs promotes autophagy activation, enhances phagosomal maturation and antimicrobial responses against mycobacterial infection. In macrophages, the GABAergic defense is mediated via macrophage type A GABA receptor (GABAAR), intracellular calcium release, and the GABA type A receptor-associated protein-like 1 (GABARAPL1; an Atg8 homolog). Finally, GABAergic inhibition increases bacterial loads in mice and zebrafish in vivo, suggesting that the GABAergic defense plays an essential function in metazoan host defenses. Our study identified a previously unappreciated role for GABAergic signaling in linking antibacterial autophagy to enhance host innate defense against intracellular bacterial infection.

Highlights

Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain; the roles of GABA in antimicrobial host defenses are largely unknown
THIP (1–30 μM) generated tonic GABAA current in a concentration-dependent manner in the presence of GABA (100 μM), THIP alone failed to significantly alter the holding current of bone marrow-derived macrophages (BMDMs). These results suggest that BMDMs express functional GABAARs that respond by generating tonic currents when exposed to GABA
Our data demonstrate that GABAergic activation promotes antimicrobial host defenses, whereas GABAergic inhibition increased the overall susceptibility to infection and bacterial loads both in vitro and in vivo

Summary

Introduction

Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain; the roles of GABA in antimicrobial host defenses are largely unknown. Our study identified a previously unappreciated role for GABAergic signaling in linking antibacterial autophagy to enhance host innate defense against intracellular bacterial infection. Given the potential role for GABA in the modulation of innate immune responses, it is poorly understood whether and how GABAergic signaling regulates antimicrobial host defenses in the context of bacterial infections. The innate immune system regulates numerous host defense pathways, innate sensing, signal transduction, and the secretion of a variety of effector molecules, including antimicrobial proteins[9,10]. We further showed that GABAergic defenses are mediated by host autophagy activation via the macrophage type A GABA receptor (GABAAR), intracellular calcium increase, and AMP-activated protein kinase (AMPK) signaling. GABAergic inhibition increased bacterial loads and host susceptibility to intracellular bacterial infections in mice and zebrafish, suggesting that GABAergic signaling-associated autophagy plays a conserved function in metazoan host defense

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Results

Conclusion