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Neuroimmunomodulation in Major Depressive Disorder: Focus on Caspase 1, Inducible Nitric Oxide Synthase, and Interferon-Gamma.

ABSTRACT: Major depressive disorder (MDD) is one of the leading causes of disability worldwide, and its incidence is expected to increase. Despite tremendous efforts to understand its underlying biological mechanisms, MDD pathophysiology remains elusive and pharmacotherapy outcomes are still far from ideal. Low-grade chronic inflammation seems to play a key role in mediating the interface between psychological stress, depressive symptomatology, altered intestinal microbiology, and MDD onset. We review the available pre-clinical and clinical evidence of an involvement of pro-inflammatory pathways in the pathogenesis, treatment, and remission of MDD. We focus on caspase 1, inducible nitric oxide synthase, and interferon gamma, three inflammatory systems dysregulated in MDD. Treatment strategies aiming at targeting such pathways alone or in combination with classical therapies could prove valuable in MDD. Further studies are needed to assess the safety and efficacy of immune modulation in MDD and other psychiatric disorders with neuroinflammatory components.

SUBMITTER: Inserra A

PROVIDER: S-EPMC6505498 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Neuroimmunomodulation in Major Depressive Disorder: Focus on Caspase 1, Inducible Nitric Oxide Synthase, and Interferon-Gamma.

Inserra Antonio A Mastronardi Claudio Alberto CA Rogers Geraint G Licinio Julio J Wong Ma-Li ML

Molecular neurobiology 20181010 6

Major depressive disorder (MDD) is one of the leading causes of disability worldwide, and its incidence is expected to increase. Despite tremendous efforts to understand its underlying biological mechanisms, MDD pathophysiology remains elusive and pharmacotherapy outcomes are still far from ideal. Low-grade chronic inflammation seems to play a key role in mediating the interface between psychological stress, depressive symptomatology, altered intestinal microbiology, and MDD onset. We review the ...[more]

PMID: 30306457

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Project description:Interferon gamma (IFN-?) restricts the intracellular replication of many pathogens, but the mechanism by which IFN-? confers cell-intrinsic pathogen resistance remains unclear. For example, intracellular replication of the bacterial pathogen Legionella pneumophila in macrophages is potently curtailed by IFN-?. However, consistent with prior studies, no individual genetic deficiency that we tested completely abolished IFN-?-mediated control. Intriguingly, we observed that the glycolysis inhibitor 2-deoxyglucose (2DG) partially rescued L. pneumophila replication in IFN-?-treated macrophages. 2DG inhibits glycolysis and triggers the unfolded protein response, but unexpectedly, it appears these effects are not responsible for perturbing the antimicrobial activity of IFN-?. Instead, we found that 2DG rescues bacterial replication by inhibiting the expression of two key antimicrobial factors, inducible nitric oxide synthase (iNOS) and immune-responsive gene 1 (IRG1). Using immortalized and primary macrophages deficient in iNOS and IRG1, we confirmed that loss of both iNOS and IRG1, but not individual deficiency in either gene, partially reduced IFN-?-mediated restriction of L. pneumophila Further, using a combinatorial CRISPR/Cas9 mutagenesis approach, we found that mutation of iNOS and IRG1 in combination with four other genes (CASP11, IRGM1, IRGM3, and NOX2) resulted in a total loss of L. pneumophila restriction by IFN-? in primary bone marrow macrophages. Our study defines a complete set of cell-intrinsic factors required for IFN-?-mediated restriction of an intracellular bacterial pathogen and highlights the combinatorial strategy used by hosts to block bacterial replication in macrophages.IMPORTANCE Legionella pneumophila is one example among many species of pathogenic bacteria that replicate within mammalian macrophages during infection. The immune signaling factor interferon gamma (IFN-?) blocks L. pneumophila replication in macrophages and is an essential component of the immune response to L. pneumophila and other intracellular pathogens. However, to date, no study has identified the exact molecular factors induced by IFN-? that are required for its activity. We generated macrophages lacking different combinations of IFN-?-induced genes in an attempt to find a genetic background in which there is a complete loss of IFN-?-mediated restriction of L. pneumophila We identified six genes that comprise the totality of the IFN-?-dependent restriction of L. pneumophila replication in macrophages. Our results clarify the molecular basis underlying the potent effects of IFN-? and highlight how redundancy downstream of IFN-? is key to prevent exploitation of macrophages by pathogens.

Project description:UnlabelledInducible nitric oxide synthase (iNOS) activity increases in acute and chronic inflammatory lung diseases. Imaging iNOS expression may be useful as an inflammation biomarker for monitoring lung disease activity. We developed a novel tracer for PET that binds to iNOS in vivo, (18)F-NOS. In this study, we tested whether (18)F-NOS could quantify iNOS expression from endotoxin-induced lung inflammation in healthy volunteers.MethodsHealthy volunteers were screened to exclude cardiopulmonary disease. Qualifying volunteers underwent a baseline, 1-h dynamic (18)F-NOS PET/CT scan. Endotoxin (4 ng/kg) was then instilled bronchoscopically in the right middle lobe. (18)F-NOS imaging was performed again approximately 16 h after endotoxin instillation. Radiolabeled metabolites were determined from blood samples. Cells recovered by bronchoalveolar lavage (BAL) after imaging were stained immunohistochemically for iNOS. (18)F-NOS uptake was quantified as the distribution volume ratio (DVR) determined by Logan plot graphical analysis in volumes of interest placed over the area of endotoxin instillation and in an equivalent lung region on the left. The mean Hounsfield units (HUs) were also computed using the same volumes of interest to measure density changes.ResultsSeven healthy volunteers with normal pulmonary function completed the study with evaluable data. The DVR increased by approximately 30%, from a baseline mean of 0.42 ± 0.07 to 0.54 ± 0.12, and the mean HUs by 11% after endotoxin in 6 volunteers who had positive iNOS staining in BAL cells. The DVR did not change in the left lung after endotoxin. In 1 volunteer with low-level iNOS staining in BAL cells, the mean HUs increased by 7% without an increase in DVR. Metabolism was rapid, with approximately 50% of the parent compound at 5 min and 17% at 60 min after injection.Conclusion(18)F-NOS can be used to image iNOS activity in acute lung inflammation in humans and may be a useful PET tracer for imaging iNOS expression in inflammatory lung disease.

Dataset Information

Neuroimmunomodulation in Major Depressive Disorder: Focus on Caspase 1, Inducible Nitric Oxide Synthase, and Interferon-Gamma.

Publications

Neuroimmunomodulation in Major Depressive Disorder: Focus on Caspase 1, Inducible Nitric Oxide Synthase, and Interferon-Gamma.

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