Autocrine GABA signaling distinctively regulates phenotypic activation of mouse pulmonary macrophages

Januzi, Luan; Poirier, Jacob W; Maksoud, Matthew J. E.; Yun, Xiang; Veldhuizen, Rudolf A.W.; Gill, Sean E.; Cregan, Sean P.; Zhang, Haibo; Dekaban, Gregory A.; Lu, Wei‐Yang

doi:10.1016/j.cellimm.2018.07.001

Cited by 36 publications

(32 citation statements)

References 55 publications

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“…Our study provides the first exhaustive characterization of a GABAergic machinery in myeloid mononuclear phagocytes. Recent findings also indicate GABAergic responses by macrophages (46), microglia (44), lymphocytes (43), and bovine immune cells (45).…”

Section: Gene Silencing Of Gaba-a R Subunits Inhibits DC Hypermotilitmentioning

confidence: 92%

A motogenic GABAergic system of mononuclear phagocytes facilitates dissemination of coccidian parasites

Bhandage

Olivera

Kanatani

et al. 2020

eLife

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Gamma-aminobutyric acid (GABA) serves diverse biological functions in prokaryotes and eukaryotes, including neurotransmission in vertebrates. Yet, the role of GABA in the immune system has remained elusive. Here, a comprehensive characterization of human and murine myeloid mononuclear phagocytes revealed the presence of a conserved and tightly regulated GABAergic machinery with expression of GABA metabolic enzymes and transporters, GABA-A receptors and regulators, and voltage-dependent calcium channels. Infection challenge with the common coccidian parasites Toxoplasma gondii and Neospora caninum activated GABAergic signaling in phagocytes. Using gene silencing and pharmacological modulators in vitro and in vivo in mice, we identify the functional determinants of GABAergic signaling in parasitized phagocytes and demonstrate a link to calcium responses and migratory activation. The findings reveal a regulatory role for a GABAergic signaling machinery in the host-pathogen interplay between phagocytes and invasive coccidian parasites. The co-option of GABA underlies colonization of the host by a Trojan horse mechanism.

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Section: Gene Silencing Of Gaba-a R Subunits Inhibits DC Hypermotilitmentioning

confidence: 92%

A motogenic GABAergic system of mononuclear phagocytes facilitates dissemination of coccidian parasites

Bhandage

Olivera

Kanatani

et al. 2020

eLife

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“…In this work, we confirm that macrophages, especially M1 macrophages, were significantly elevated in the aortic wall of AAA; meanwhile, intriguingly, we found that the concentration of serum GABA was reduced in AAA patients compared with people without AAA. GABA is a paramount immunomodulatory molecule, and its signaling regulates the effects of some immune cells ( Bhandage et al, 2018 ; Januzi et al, 2018 ). Topiramate, which is a specific GABA A receptor agonist, has been noted to be associated with macrophage polarization ( Wang et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…Prior study has suggested that topiramate can inhibit the formation of human macrophage-derived foam cells ( Yang et al, 2014 ). In mouse pulmonary macrophages, during INFγ-induced M1-like activation, GABA signaling is down-regulated; with the GABA A receptor agonist, these M1-like responses are significantly prevented ( Januzi et al, 2018 ). Recent research demonstrated that GABA A receptor agonist modulates post-infarction inflammation by changing the ratio of M1/M2 ( Wang et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Modulating Neuro-Immune-Induced Macrophage Polarization With Topiramate Attenuates Experimental Abdominal Aortic Aneurysm

Chen

Xiao

et al. 2020

Front. Pharmacol.

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The development of abdominal aortic aneurysm (AAA) is attributed to psychological and physical factors. Topiramate, which is an agonist of the GABA A receptor, makes contributions to neuronal disease and is partially involved in immune regulation, may be effective upon abdominal aortic aneurysm progression. We used experimental abdominal aortic aneurysm models: Angiotensin II (Ang II)–induced ApoE −/− male mice (Ang II/APOE model) in our study. In the Ang II/APOE model, all mice (n=64) were divided into four groups: sham group (PBS treatment), control group (Ang II treatment), low-dose group (Ang II + low-dose topiramate, 3 mg/day per mouse), and high-dose group (Ang II + high-dose topiramate, 6 mg/day per mouse). All treatments began on the day after surgery. Moreover, collected tissues and cultured cell were used for histology and biochemical examination. In vitro , the effects of topiramate on bone marrow-derived macrophage stimulated by LPS were investigated. Our data implied that topiramate treatment significantly promoted macrophages preservation and conversion of M1 to M2 macrophage phenotypes in vivo and in vitro . Accordingly, proinflammatory activities mediated by the M1 macrophages were decreased and the repair process mediated by M2 macrophages was enhanced. The low-dose and high-dose groups had abdominal aortic aneurysm incidences of 50% and 37.5%, respectively, compared with 75% in the control group. Topiramate, a promising drug for the psychological disease, that target neuro-immune-induced macrophage polarization may attenuate experimental abdominal aortic aneurysm progression.

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“…The biological roles of GABA-Rs on immune cells are not yet well understood, but there is a growing body of evidence that the activation of these receptors has immunoregulatory actions. Rodent and human macrophages and dendric cells express GABA-Rs and GABA-R agonists inhibit their inflammatory activities (1)(2)(3)(4)(5)(6). T cells also express GABA-Rs (4)(5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

GABA administration limits viral replication and pneumonitis in a mouse model of COVID-19

Tian

Middleton

2021

Preprint

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Despite the availability of vaccines for COVID-19, serious illness and death induced by coronavirus infection will remain a global health burden because of vaccination hesitancy, possible virus mutations, and the appearance of novel coronaviruses. Accordingly, there is a need for new approaches to limit severe illness stemming from coronavirus infections. Cells of the immune system and lung epithelia express receptors for GABA (GABA-Rs), a widely used neurotransmitter within the CNS. GABA-R agonists have anti-inflammatory effects and can limit acute lung injury. We previously showed that GABA treatment effectively reduced disease severity and death rates in mice following infection with a coronavirus (MHV-1) which provides a potentially lethal model of COVID-19. Here, we report that GABA treatment also reduced viral load in the lungs, suggesting that GABA-Rs may provide a new druggable target to limit pulmonary coronavirus replication. Histopathological analysis revealed that GABA treatment reduced lung inflammatory infiltrates and damages. Since GABA is safe for human consumption, inexpensive, and available worldwide, it is a promising candidate to help treat COVID-19.

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Autocrine GABA signaling distinctively regulates phenotypic activation of mouse pulmonary macrophages

Cited by 36 publications

References 55 publications

A motogenic GABAergic system of mononuclear phagocytes facilitates dissemination of coccidian parasites

A motogenic GABAergic system of mononuclear phagocytes facilitates dissemination of coccidian parasites

Modulating Neuro-Immune-Induced Macrophage Polarization With Topiramate Attenuates Experimental Abdominal Aortic Aneurysm

GABA administration limits viral replication and pneumonitis in a mouse model of COVID-19

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