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

• Published in: Nature communications Vol. 9; no. 1; pp. 4184 - 17
• Main Authors: Kim, Jin Kyung, Kim, Yi Sak, Lee, Hye-Mi, Jin, Hyo Sun, Neupane, Chiranjivi, Kim, Sup, Lee, Sang-Hee, Min, Jung-Joon, Sasai, Miwa, Jeong, Jae-Ho, Choe, Seong-Kyu, Kim, Jin-Man, Yamamoto, Masahiro, Choy, Hyon E, Park, Jin Bong, Jo, Eun-Kyeong
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 10.10.2018; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adenylate Kinase - metabolism; Animals; Anti-Bacterial Agents - pharmacology; Antiinfectives and antibacterials; Autophagy; Autophagy - drug effects; Bacteria; Bacterial infections; Bacterial Infections - metabolism; Bacterial Infections - pathology; Brain; Calcium; Calcium (intracellular); Calcium - metabolism; Cell activation; gamma-Aminobutyric Acid - metabolism; Homology; Host-Pathogen Interactions - drug effects; Humans; Infections; Intracellular; Intracellular signalling; Macrophages; Macrophages - metabolism; Macrophages - ultrastructure; Mice, Inbred C57BL; Microtubule-Associated Proteins - metabolism; Mycobacterium tuberculosis - drug effects; Phagocytosis; Phagosomes - drug effects; Phagosomes - metabolism; Phagosomes - ultrastructure; Proteins; Receptors, GABA - metabolism; Signal Transduction - drug effects; Zebrafish; γ-Aminobutyric acid A receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-06487-5

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 (GABA R), 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.