Gamma-aminobutyric acid type A receptor alpha 4 coordinates autophagy, inflammation, and immunometabolism to promote innate immune activation
Gamma-aminobutyric acid type A receptor (GABAAR), the ionotropic receptor of GABA, is expressed in macrophages and in the nervous system; however, its role in innate immunity is unknown. Herein, we identified myeloid GABAAR subunit α4 (Gabra4) as a critical regulator of autophagy and a promoter of h...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Autophagy Reports |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/27694127.2023.2181915 |
| _version_ | 1797685714981224448 |
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| author | Jin Kyung Kim Prashanta Silwal Young Jae Kim Sang Min Jeon In Soo Kim June-Young Lee Jun Young Heo Sang-Hee Lee Jin-Woo Bae Jin-Man Kim Jin Bong Park Eun-Kyeong Jo |
| author_facet | Jin Kyung Kim Prashanta Silwal Young Jae Kim Sang Min Jeon In Soo Kim June-Young Lee Jun Young Heo Sang-Hee Lee Jin-Woo Bae Jin-Man Kim Jin Bong Park Eun-Kyeong Jo |
| author_sort | Jin Kyung Kim |
| collection | DOAJ |
| description | Gamma-aminobutyric acid type A receptor (GABAAR), the ionotropic receptor of GABA, is expressed in macrophages and in the nervous system; however, its role in innate immunity is unknown. Herein, we identified myeloid GABAAR subunit α4 (Gabra4) as a critical regulator of autophagy and a promoter of host innate defense during infection and inflammation. Myeloid Gabra4 deficiency led to defective mycobacterial clearance during infection and increased susceptibility to septic shock. Gabra4 deletion exaggerated inflammatory responses and suppressed the activation of autophagy in macrophages upon infectious and inflammatory stimuli. Mechanistically, Gabra4-mediated signaling led to upregulation of autophagy in macrophages via intracellular calcium release and AMP-activated protein kinase (AMPK) signaling activation, which was required for linking autophagy and antimicrobial responses. Additionally, Gabra4 was required to generate mitochondrial reactive oxygen species, thereby triggering autophagy and antimicrobial responses to mycobacteria. Metabolomics analysis showed that Gabra4 was critical for glucose metabolism and aerobic glycolysis in macrophages. Our findings demonstrate that myeloid Gabra4 coordinates autophagy, inflammation, and immunometabolism to promote innate host defense against pathogenic and dangerous stimuli. Abbreviation AM: Alveolar macrophage; AMPK: AMP-activated protein kinase; ASC: Apoptosis-associated speck-like protein containing a CARD; ATP: Adenosine 5’-triphosphate; BAL: Bronchoalveolar lavage; BCG: Mycobacterium bovis Bacillus Calmette–Guérin; BMDM: Bone marrow-derived macrophage; CCL: CC motif chemokine ligand; CFU: Colony forming unit; CKO: Conditional knock out; CXCL: C-X-C motif ligand; Dpi: Days post-infection; ECAR: Extracellular acidification rate; EGFP: Enhanced green fluorescent protein; FOXO3: Forkhead box O3; GABA: Gamma-aminobutyric acid; GABAAR: GABA type A receptor; Gabarap: GABA type A receptor-associated protein; Gabarapl1: GABA type A receptor-associated protein like 1; GABRA4: Gamma-aminobutyric acid type A receptor subunit alpha4; HIF-1α: Hypoxia-inducible factor-1 alpha; IL: Interleukin; i.n.: Intranasal; i.p.: Intraperitoneal; LDHA: Lactate dehydrogenase A; LPS: Lipopolysaccharide; Mabc: Mycobacteroides abscessus subsp. abscessus; MOI: Multiplicities of infection; Mtb: Mycobacterium tuberculosis; mtROS: Mitochondrial reactive oxygen species; OCR: Oxygen consumption rate; OXPHOS: Oxidative phosphorylation; PM: Peritoneal macrophage; TNF: Tumor necrosis factor; WT: Wild type |
| first_indexed | 2024-03-12T00:55:18Z |
| format | Article |
| id | doaj.art-93629026a01e44d08b5dff1516a0aed7 |
| institution | Directory Open Access Journal |
| issn | 2769-4127 |
| language | English |
| last_indexed | 2024-03-12T00:55:18Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Autophagy Reports |
| spelling | doaj.art-93629026a01e44d08b5dff1516a0aed72023-09-14T13:24:41ZengTaylor & Francis GroupAutophagy Reports2769-41272023-12-012110.1080/27694127.2023.21819152181915Gamma-aminobutyric acid type A receptor alpha 4 coordinates autophagy, inflammation, and immunometabolism to promote innate immune activationJin Kyung Kim0Prashanta Silwal1Young Jae Kim2Sang Min Jeon3In Soo Kim4June-Young Lee5Jun Young Heo6Sang-Hee Lee7Jin-Woo Bae8Jin-Man Kim9Jin Bong Park10Eun-Kyeong Jo11Keimyung University School of MedicineChungnam National University School of MedicineChungnam National University School of MedicineChungnam National University School of MedicineChungnam National University School of MedicineKyung Hee UniversityInfection Control Convergence Research Center, Chungnam National University School of MedicineCenter for Research Equipment, Korea Basic Science InstituteKyung Hee UniversityChungnam National University School of MedicineChungnam National University School of MedicineChungnam National University School of MedicineGamma-aminobutyric acid type A receptor (GABAAR), the ionotropic receptor of GABA, is expressed in macrophages and in the nervous system; however, its role in innate immunity is unknown. Herein, we identified myeloid GABAAR subunit α4 (Gabra4) as a critical regulator of autophagy and a promoter of host innate defense during infection and inflammation. Myeloid Gabra4 deficiency led to defective mycobacterial clearance during infection and increased susceptibility to septic shock. Gabra4 deletion exaggerated inflammatory responses and suppressed the activation of autophagy in macrophages upon infectious and inflammatory stimuli. Mechanistically, Gabra4-mediated signaling led to upregulation of autophagy in macrophages via intracellular calcium release and AMP-activated protein kinase (AMPK) signaling activation, which was required for linking autophagy and antimicrobial responses. Additionally, Gabra4 was required to generate mitochondrial reactive oxygen species, thereby triggering autophagy and antimicrobial responses to mycobacteria. Metabolomics analysis showed that Gabra4 was critical for glucose metabolism and aerobic glycolysis in macrophages. Our findings demonstrate that myeloid Gabra4 coordinates autophagy, inflammation, and immunometabolism to promote innate host defense against pathogenic and dangerous stimuli. Abbreviation AM: Alveolar macrophage; AMPK: AMP-activated protein kinase; ASC: Apoptosis-associated speck-like protein containing a CARD; ATP: Adenosine 5’-triphosphate; BAL: Bronchoalveolar lavage; BCG: Mycobacterium bovis Bacillus Calmette–Guérin; BMDM: Bone marrow-derived macrophage; CCL: CC motif chemokine ligand; CFU: Colony forming unit; CKO: Conditional knock out; CXCL: C-X-C motif ligand; Dpi: Days post-infection; ECAR: Extracellular acidification rate; EGFP: Enhanced green fluorescent protein; FOXO3: Forkhead box O3; GABA: Gamma-aminobutyric acid; GABAAR: GABA type A receptor; Gabarap: GABA type A receptor-associated protein; Gabarapl1: GABA type A receptor-associated protein like 1; GABRA4: Gamma-aminobutyric acid type A receptor subunit alpha4; HIF-1α: Hypoxia-inducible factor-1 alpha; IL: Interleukin; i.n.: Intranasal; i.p.: Intraperitoneal; LDHA: Lactate dehydrogenase A; LPS: Lipopolysaccharide; Mabc: Mycobacteroides abscessus subsp. abscessus; MOI: Multiplicities of infection; Mtb: Mycobacterium tuberculosis; mtROS: Mitochondrial reactive oxygen species; OCR: Oxygen consumption rate; OXPHOS: Oxidative phosphorylation; PM: Peritoneal macrophage; TNF: Tumor necrosis factor; WT: Wild typehttp://dx.doi.org/10.1080/27694127.2023.2181915gabra4mycobacteriainfectioninflammationampkmacrophagesmitochondrial oxidative phosphorylationimmunometabolismsepsis |
| spellingShingle | Jin Kyung Kim Prashanta Silwal Young Jae Kim Sang Min Jeon In Soo Kim June-Young Lee Jun Young Heo Sang-Hee Lee Jin-Woo Bae Jin-Man Kim Jin Bong Park Eun-Kyeong Jo Gamma-aminobutyric acid type A receptor alpha 4 coordinates autophagy, inflammation, and immunometabolism to promote innate immune activation Autophagy Reports gabra4 mycobacteria infection inflammation ampk macrophages mitochondrial oxidative phosphorylation immunometabolism sepsis |
| title | Gamma-aminobutyric acid type A receptor alpha 4 coordinates autophagy, inflammation, and immunometabolism to promote innate immune activation |
| title_full | Gamma-aminobutyric acid type A receptor alpha 4 coordinates autophagy, inflammation, and immunometabolism to promote innate immune activation |
| title_fullStr | Gamma-aminobutyric acid type A receptor alpha 4 coordinates autophagy, inflammation, and immunometabolism to promote innate immune activation |
| title_full_unstemmed | Gamma-aminobutyric acid type A receptor alpha 4 coordinates autophagy, inflammation, and immunometabolism to promote innate immune activation |
| title_short | Gamma-aminobutyric acid type A receptor alpha 4 coordinates autophagy, inflammation, and immunometabolism to promote innate immune activation |
| title_sort | gamma aminobutyric acid type a receptor alpha 4 coordinates autophagy inflammation and immunometabolism to promote innate immune activation |
| topic | gabra4 mycobacteria infection inflammation ampk macrophages mitochondrial oxidative phosphorylation immunometabolism sepsis |
| url | http://dx.doi.org/10.1080/27694127.2023.2181915 |
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