Gamma-aminobutyric acid type A receptor alpha 4 coordinates autophagy, inflammation, and immunometabolism to promote innate immune activation

References

• Hamze M, Medina I, Delmotte Q, et al. Contribution of Smoothened Receptor Signaling in GABAergic Neurotransmission and Chloride Homeostasis in the Developing Rodent Brain. Front Physiol. 2021;12:798066.
   PubMed Web of Science ®Google Scholar
• Bhandage AK, Barragan A. GABAergic signaling by cells of the immune system: more the rule than the exception. Cell Mol Life Sci. 2021;78(15):5667–38.
   PubMed Web of Science ®Google Scholar
• Kim JK, Kim YS, Lee HM, et al. GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections. Nat Commun. 2018;9(1):4184.
   PubMedGoogle Scholar
• Zhang B, Vogelzang A, Miyajima M, et al. B cell-derived GABA elicits IL-10(+) macrophages to limit anti-tumour immunity. Nature. 2021;599(7885):471–476.
   PubMed Web of Science ®Google Scholar
• Xia Y, He F, Wu X, et al. GABA transporter sustains IL-1beta production in macrophages. Sci Adv. 2021;7(15).
   Web of Science ®Google Scholar
• Hannan S, Minere M, Harris J, et al. GABAAR isoform and subunit structural motifs determine synaptic and extrasynaptic receptor localisation. Neuropharmacology. 2020;169:107540.
   PubMed Web of Science ®Google Scholar
• Maguire EP, Macpherson T, Swinny JD, et al. Tonic inhibition of accumbal spiny neurons by extrasynaptic alpha4betadelta GABAA receptors modulates the actions of psychostimulants. J Neurosci. 2014;34(3):823–38.
   PubMed Web of Science ®Google Scholar
• Sallard E, Letourneur D, Legendre P. Electrophysiology of ionotropic GABA receptors. Cell Mol Life Sci. 2021;78(13):5341–5370.
   PubMed Web of Science ®Google Scholar
• Mills DJ. The Aging GABAergic System and Its Nutritional Support. J Nutr Metab. 2021;2021:6655064.
   PubMed Web of Science ®Google Scholar
• Knott EL, Leidenheimer NJ. A Targeted Bioinformatics Assessment of Adrenocortical Carcinoma Reveals Prognostic Implications of GABA System Gene Expression. Int J Mol Sci. 2020;21(22).
   Web of Science ®Google Scholar
• Prud’homme GJ, Glinka Y, Wang Q. Immunological GABAergic interactions and therapeutic applications in autoimmune diseases. Autoimmun Rev. 2015;14(11):1048–56.
   PubMed Web of Science ®Google Scholar
• Auteri M, Zizzo MG, Serio R. GABA and GABA receptors in the gastrointestinal tract: from motility to inflammation. Pharmacol Res. 2015;93:11–21.
   PubMed Web of Science ®Google Scholar
• Jin Z, Mendu SK, Birnir B. GABA is an effective immunomodulatory molecule. Amino Acids. 2013;45(1):87–94.
   PubMed Web of Science ®Google Scholar
• Comenencia-Ortiz E, Moss SJ, Davies PA. Phosphorylation of GABAA receptors influences receptor trafficking and neurosteroid actions. Psychopharmacology (Berl). 2014;231(17):3453–65.
   PubMed Web of Science ®Google Scholar
• Hines RM, Davies PA, Moss SJ, et al. Functional regulation of GABAA receptors in nervous system pathologies. Curr Opin Neurobiol. 2012;22(3):552–8.
   PubMed Web of Science ®Google Scholar
• Reddy DS. GABA-A Receptors Mediate Tonic Inhibition and Neurosteroid Sensitivity in the Brain. Vitam Horm. 2018;107:177–191.
   PubMed Web of Science ®Google Scholar
• Othman A, Sekheri M, Filep JG. Roles of neutrophil granule proteins in orchestrating inflammation and immunity. FEBS J. 2021.
   Google Scholar
• Paludan SR, Pradeu T, Masters SL, et al. Constitutive immune mechanisms: mediators of host defence and immune regulation. Nat Rev Immunol. 2021;21(3):137–150.
   PubMed Web of Science ®Google Scholar
• Deretic V. Autophagy in inflammation, infection, and immunometabolism. Immunity. 2021;54(3):437–453.
   PubMed Web of Science ®Google Scholar
• Klionsky DJ, Petroni G, Amaravadi RK, et al. Autophagy in major human diseases. EMBO J. 2021;40(19):e108863.
   PubMed Web of Science ®Google Scholar
• Mizushima N, Levine B. Autophagy in Human Diseases. N Engl J Med. 2020;383(16):1564–1576.
   PubMed Web of Science ®Google Scholar
• Deretic V, Levine B. Autophagy balances inflammation in innate immunity. Autophagy. 2018;14(2):243–251.
   PubMed Web of Science ®Google Scholar
• Cadwell K. Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis. Nat Rev Immunol. 2016;16(11):661–675.
   PubMed Web of Science ®Google Scholar
• Rao L, Eissa NT. Autophagy in Pulmonary Innate Immunity. J Innate Immun. 2020;12(1):21–30.
   PubMed Web of Science ®Google Scholar
• Saitoh T, Akira S. Regulation of inflammasomes by autophagy. J Allergy Clin Immunol. 2016;138(1):28–36.
   PubMed Web of Science ®Google Scholar
• Rodgers MA, Bowman JW, Liang Q, et al. Regulation where autophagy intersects the inflammasome. Antioxid Redox Signal. 2014;20(3):495–506.
   PubMed Web of Science ®Google Scholar
• Paik S, Jo EK. An Interplay Between Autophagy and Immunometabolism for Host Defense Against Mycobacterial Infection. Front Immunol. 2020;11:603951.
   PubMed Web of Science ®Google Scholar
• Kim JK, Silwal P, Jo EK. Host-Pathogen Dialogues in Autophagy, Apoptosis, and Necrosis during Mycobacterial Infection. Immune Netw. 2020;20(5):e37.
   PubMed Web of Science ®Google Scholar
• Kiran D, Podell BK, Chambers M, et al. Host-directed therapy targeting the Mycobacterium tuberculosis granuloma: a review. Semin Immunopathol. 2016;38(2):167–83.
   PubMed Web of Science ®Google Scholar
• Kim TS, Jin YB, Kim YS, et al. SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions. Autophagy. 2019;15(8):1356–1375.
   PubMed Web of Science ®Google Scholar
• Kimmey JM, Huynh JP, Weiss LA, et al. Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection. Nature. 2015;528(7583):565–9.
   PubMed Web of Science ®Google Scholar
• Nouailles G, Dorhoi A, Koch M, et al. CXCL5-secreting pulmonary epithelial cells drive destructive neutrophilic inflammation in tuberculosis. J Clin Invest. 2014;124(3):1268–82.
   PubMed Web of Science ®Google Scholar
• Schaaf MB, Keulers TG, Vooijs MA, et al. LC3/GABARAP family proteins: autophagy-(un)related functions. FASEB J. 2016;30(12):3961–3978.
   PubMed Web of Science ®Google Scholar
• Sanchez AM, Csibi A, Raibon A, et al. AMPK promotes skeletal muscle autophagy through activation of forkhead FoxO3a and interaction with Ulk1. J Cell Biochem. 2012;113(2):695–710.
   PubMed Web of Science ®Google Scholar
• Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol. 2018;19(2):121–135.
   PubMed Web of Science ®Google Scholar
• Fukai T, Ushio-Fukai M. Cross-Talk between NADPH Oxidase and Mitochondria: Role in ROS Signaling and Angiogenesis. Cells. 2020;9(8).
   Web of Science ®Google Scholar
• Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417(1):1–13.
   PubMed Web of Science ®Google Scholar
• Dan Dunn J, Alvarez LA, Zhang X, et al. Reactive oxygen species and mitochondria: A nexus of cellular homeostasis. Redox Biol. 2015;6:472–485.
   PubMed Web of Science ®Google Scholar
• Drasbek KR, Jensen K. THIP, a hypnotic and antinociceptive drug, enhances an extrasynaptic GABAA receptor-mediated conductance in mouse neocortex. Cereb Cortex. 2006;16(8):1134–41.
   PubMed Web of Science ®Google Scholar
• O’Neill LA, Pearce EJ. Immunometabolism governs dendritic cell and macrophage function. J Exp Med. 2016;213(1):15–23.
   PubMed Web of Science ®Google Scholar
• Jha AK, Huang SC, Sergushichev A, et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity. 2015;42(3):419–30.
   PubMed Web of Science ®Google Scholar
• Shi X, Tan S, Tan S. NLRP3 inflammasome in sepsis (Review). Mol Med Rep. 2021;24(1).
   Web of Science ®Google Scholar
• Zhao S, Chen F, Yin Q, et al. Reactive Oxygen Species Interact With NLRP3 Inflammasomes and Are Involved in the Inflammation of Sepsis: From Mechanism to Treatment of Progression. Front Physiol. 2020;11:571810.
   PubMed Web of Science ®Google Scholar
• Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19(8):477–489.
   PubMed Web of Science ®Google Scholar
• Olsen RW, Sieghart W. GABA A receptors: subtypes provide diversity of function and pharmacology. Neuropharmacology. 2009;56(1):141–8.
   PubMed Web of Science ®Google Scholar
• Bhandage AK, Olivera GC, Kanatani S, et al. A motogenic GABAergic system of mononuclear phagocytes facilitates dissemination of coccidian parasites. Elife. 2020;9.
   Google Scholar
• Yocum GT, Turner DL, Danielsson J, et al. GABAA receptor alpha4-subunit knockout enhances lung inflammation and airway reactivity in a murine asthma model. Am J Physiol Lung Cell Mol Physiol. 2017;313(2):L406–L415.
   PubMed Web of Science ®Google Scholar
• Wheeler DW, Thompson AJ, Corletto F, et al. Anaesthetic impairment of immune function is mediated via GABA(A) receptors. PLoS One. 2011;6(2):e17152.
   PubMed Web of Science ®Google Scholar
• Bohnsack JP, Carlson SL, Morrow AL. Differential regulation of synaptic and extrasynaptic alpha4 GABA(A) receptor populations by protein kinase A and protein kinase C in cultured cortical neurons. Neuropharmacology. 2016;105:124–132.
   PubMed Web of Science ®Google Scholar
• Delgado-Lezama R, Loeza-Alcocer E, Andres C, et al. Extrasynaptic GABA(A) receptors in the brainstem and spinal cord: structure and function. Curr Pharm Des. 2013;19(24):4485–97.
   PubMed Web of Science ®Google Scholar
• Fuks JM, Arrighi RB, Weidner JM, et al. GABAergic signaling is linked to a hypermigratory phenotype in dendritic cells infected by Toxoplasma gondii. PLoS Pathog. 2012;8(12):e1003051.
   PubMed Web of Science ®Google Scholar
• Bhandage AK, Friedrich LM, Kanatani S, et al. GABAergic signaling in human and murine NK cells upon challenge with Toxoplasma gondii. J Leukoc Biol. 2021;110(4):617–628.
   PubMed Web of Science ®Google Scholar
• Hagenbuchner J, Ausserlechner MJ. Mitochondria and FOXO3: breath or die. Front Physiol. 2013;4:147.
   PubMed Web of Science ®Google Scholar
• Ferber EC, Peck B, Delpuech O, et al. FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression. Cell Death Differ. 2012;19(6):968–79.
   PubMed Web of Science ®Google Scholar
• Salih DA, Brunet A. FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol. 2008;20(2):126–36.
   PubMed Web of Science ®Google Scholar
• Cheng Z. The FoxO-Autophagy Axis in Health and Disease. Trends Endocrinol Metab. 2019;30(9):658–671.
   PubMed Web of Science ®Google Scholar
• Audesse AJ, Dhakal S, Hassell LA, et al. FOXO3 directly regulates an autophagy network to functionally regulate proteostasis in adult neural stem cells. PLoS Genet. 2019;15(4):e1008097.
   PubMed Web of Science ®Google Scholar
• Fan J, Li D, Chen HS, et al. Metformin produces anxiolytic-like effects in rats by facilitating GABAA receptor trafficking to membrane. Br J Pharmacol. 2019;176(2):297–316.
   PubMed Web of Science ®Google Scholar
• Alam J, Deharo D, Redding KM, et al. C-terminal processing of GABARAP is not required for trafficking of the angiotensin II type 1A receptor. Regul Pept. 2010; 159 (1–3): 78–86.
   PubMedGoogle Scholar
• Li Y, Song D, Bo F, et al. Diazepam inhibited lipopolysaccharide (LPS)-induced pyroptotic cell death and alleviated pulmonary fibrosis in mice by specifically activating GABAA receptor alpha4-subunit. Biomed Pharmacother. 2019;118:109239.
   PubMed Web of Science ®Google Scholar
• Mo J, Kim CH, Lee D, et al. Early growth response 1 (Egr-1) directly regulates GABAA receptor alpha2, alpha4, and theta subunits in the hippocampus. J Neurochem. 2015;133(4):489–500.
   PubMed Web of Science ®Google Scholar
• Roberts DS, Raol YH, Bandyopadhyay S, et al. Egr3 stimulation of GABRA4 promoter activity as a mechanism for seizure-induced up-regulation of GABA(A) receptor alpha4 subunit expression. Proc Natl Acad Sci U S A. 2005;102(33):11894–9.
   PubMed Web of Science ®Google Scholar
• Patoli D, Mignotte F, Deckert V, et al. Inhibition of mitophagy drives macrophage activation and antibacterial defense during sepsis. J Clin Invest. 2020;130(11):5858–5874.
   PubMed Web of Science ®Google Scholar
• Shi L, Jiang Q, Bushkin Y, et al. Biphasic Dynamics of Macrophage Immunometabolism during Mycobacterium tuberculosis Infection. mBio. 2019;10(2).
   Web of Science ®Google Scholar
• Lachmandas E, Beigier-Bompadre M, Cheng SC, et al. Rewiring cellular metabolism via the AKT/mTOR pathway contributes to host defence against Mycobacterium tuberculosis in human and murine cells. Eur J Immunol. 2016;46(11):2574–2586.
   PubMed Web of Science ®Google Scholar
• C OM, Cox DJ, Phelan JJ, et al. Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis. Front Immunol. 2021;12:663695.
   PubMedGoogle Scholar
• Silwal P, Kim JK, Jeon SM, et al. Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice. Commun Biol. 2021;4(1):548.
   PubMed Web of Science ®Google Scholar
• Sohrabipour S, Sharifi MR, Talebi A, et al. GABA dramatically improves glucose tolerance in streptozotocin-induced diabetic rats fed with high-fat diet. Eur J Pharmacol. 2018;826:75–84.
   PubMed Web of Science ®Google Scholar
• Kim JK, Lee HM, Park KS, et al. MIR144* inhibits antimicrobial responses against Mycobacterium tuberculosis in human monocytes and macrophages by targeting the autophagy protein DRAM2. Autophagy. 2017;13(2):423–441.
   PubMed Web of Science ®Google Scholar
• Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27–30.
   PubMed Web of Science ®Google Scholar