Human lung and monocyte-derived macrophages differ with regard to the effects of β2-adrenoceptor agonists on cytokine release

Victoni, Tatiana; Salvator, Hélène; Abrial, Charlotte; Brollo, Marion; Pôrto, Luís Cristóvão; Lagente, Vincent; Naline, Emmanuel; Grassin-Delyle, Stanislas; Devillier, Philippe

doi:10.1186/s12931-017-0613-y

Cited by 19 publications

(15 citation statements)

References 57 publications

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“…Lung tissue samples were obtained from 28 patients [18 males and 10 females; smoker/ex-smoker/non-smoker: 11/16/1; mean ± standard error (SD) age: 65.4 ± 8.1 years; FEV1 = 80.2 ± 20.9%; pack-years: 41 ± 21; FEV1/FVC ratio: 0.77 ± 0.1; 7 COPD (FEV1/FVC < 0.7; airflow limitation severity: GOLD 1 for 4 patients and GOLD 2 for 3)] undergoing surgical resection for lung carcinoma and who had not received prior chemotherapy. The LMs were isolated from macroscopically normal lung parenchyma (obtained from sites distant from the tumor), dissected free of pleura, visible airways and blood vessels, and then chopped into 3–5 mm 3 fragments, as previously described (Jeyaseelan et al, 2005; Buenestado et al, 2010, 2012; Abrial et al, 2015; Victoni et al, 2017).…”

Section: Methodsmentioning

confidence: 99%

Bitter Taste Receptors (TAS2Rs) in Human Lung Macrophages: Receptor Expression and Inhibitory Effects of TAS2R Agonists

et al. 2019

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BackgroundBitter-taste receptors (TAS2Rs) are involved in airway relaxation but are also expressed in human blood leukocytes. We studied TAS2R expression and the effects of TAS2R agonists on the lipopolysaccharide (LPS)-induced cytokine release in human lung macrophages (LMs).MethodsLung macrophages were isolated from patients undergoing surgery for carcinoma. We used RT-qPCR to measure transcripts of 16 TAS2Rs (TAS2Rs 3/4/5/7/8/9/10/14/19/20/31/38/39/43/45 and 46) in unstimulated and LPS-stimulated (10 ng.mL–1) LMs. The macrophages were also incubated with TAS2R agonists for 24 h. Supernatant levels of the cytokines TNF-α, CCL3, CXCL8 and IL-10 were measured using ELISAs.ResultsThe transcripts of all 16 TAS2Rs were detected in macrophages. The addition of LPS led to an increase in the expression of most TAS2Rs, which was significant for TAS2R7 and 38. Although the promiscuous TAS2R agonists, quinine and denatonium, inhibited the LPS-induced release of TNF-α, CCL3 and CXCL8, diphenidol was inactive. Partially selective agonists (dapsone, colchicine, strychnine, and chloroquine) and selective agonists [erythromycin (TAS2R10), phenanthroline (TAS2R5), ofloxacin (TAS2R9), and carisoprodol (TAS2R14)] also suppressed the LPS-induced cytokine release. In contrast, two other agonists [sodium cromoglycate (TAS2R20) and saccharin (TAS2R31 and 43)] were inactive. TAS2R agonists suppressed IL-10 production – suggesting that this anti-inflammatory cytokine is not involved in the inhibition of cytokine production.ConclusionHuman LMs expressed TAS2Rs. Experiments with TAS2R agonists’ suggested the involvement of TAS2Rs 3, 4, 5, 9, 10, 14, 30, 39 and 40 in the inhibition of cytokine production. TAS2Rs may constitute new drug targets in inflammatory obstructive lung disease.

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Section: Methodsmentioning

confidence: 99%

Bitter Taste Receptors (TAS2Rs) in Human Lung Macrophages: Receptor Expression and Inhibitory Effects of TAS2R Agonists

et al. 2019

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“…Both in vitro and in vivo studies support the conclusion that at least one way in which β-adrenergic signaling can promote breast cancer progression is by polarizing macrophages toward an M2 phenotype ( 42 , 43 ). Moreover, in response to LPS stimulation, human monocyte-derived macrophages produce reduced amounts of the inflammatory cytokines TNF-α, IL-1β, CCL2, CCL3, and CCL4 ( 47 – 49 ) and decrease IL-27 secretion in response to acute inflammation ( 50 ) while, at the same time, increasing production of the anti-inflammatory cytokines IL-4, IL-10, and IL-13 production ( 44 , 50 ). In contrast to the effects of β-AR signaling in macrophage, α-AR signaling promotes secretion of pro-inflammatory cytokines ( 24 , 51 ).…”

Section: Neural Regulation Of the Immune Responsementioning

confidence: 99%

Adrenergic Signaling: A Targetable Checkpoint Limiting Development of the Antitumor Immune Response

et al. 2018

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An immune response must be tightly controlled so that it will be commensurate with the level of response needed to protect the organism without damaging normal tissue. The roles of cytokines and chemokines in orchestrating these processes are well known, but although stress has long been thought to also affect immune responses, the underlying mechanisms were not as well understood. Recently, the role of nerves and, specifically, the sympathetic nervous system, in regulating immune responses is being revealed. Generally, an acute stress response is beneficial but chronic stress is detrimental because it suppresses the activities of effector immune cells while increasing the activities of immunosuppressive cells. In this review, we first discuss the underlying biology of adrenergic signaling in cells of both the innate and adaptive immune system. We then focus on the effects of chronic adrenergic stress in promoting tumor growth, giving examples of effects on tumor cells and immune cells, explaining the methods commonly used to induce stress in preclinical mouse models. We highlight how this relates to our observations that mandated housing conditions impose baseline chronic stress on mouse models, which is sufficient to cause chronic immunosuppression. This problem is not commonly recognized, but it has been shown to impact conclusions of several studies of mouse physiology and mouse models of disease. Moreover, the fact that preclinical mouse models are chronically immunosuppressed has critical ramifications for analysis of any experiments with an immune component. Our group has found that reducing adrenergic stress by housing mice at thermoneutrality or treating mice housed at cooler temperatures with β-blockers reverses immunosuppression and significantly improves responses to checkpoint inhibitor immunotherapy. These observations are clinically relevant because there are numerous retrospective epidemiological studies concluding that cancer patients who were taking β-blockers have better outcomes. Clinical trials testing whether β-blockers can be repurposed to improve the efficacy of traditional and immunotherapies in patients are on the horizon.

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“…However, important phenotypic differences were already reported between such surrogates and primary macrophages. For example, distinct patterns and expression levels of G-protein coupled receptors (including cytokine receptors) and ion channels were found between monocytes, cell lines and human alveolar macrophages [50]; peripheral blood monocytes exhibit no suppression by LPS of 5-lipoxygenase metabolism and no induction of iNOS compared to alveolar macrophages [41], LPS-stimulated human alveolar macrophages produce more PGE 2 than do blood monocytes [42] and the LPS-induced cytokine production is also higher in primary lung macrophages than in MDMs https://doi.org/10.1371/journal.pone.0230813.g003 [51], highlighting the interest of confirming with primary cells the results obtained with available surrogates. In addition to molecules from arachidonic acid metabolism, pathway analysis revealed a role for the tryptophan metabolism and Krebs cycle during macrophage M1 polarisation.…”

Section: Discussionmentioning

confidence: 94%

Metabolic reprograming of LPS-stimulated human lung macrophages involves tryptophan metabolism and the aspartate-arginosuccinate shunt

et al. 2020

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Lung macrophages (LM) are in the first line of defense against inhaled pathogens and can undergo phenotypic polarization to the proinflammatory M1 after stimulation with Toll-like receptor agonists. The objective of the present work was to characterize the metabolic alterations occurring during the experimental M1 LM polarization. Human LM were obtained from resected lungs and cultured for 24 hrs in medium alone or with 10 ng.mL -1 lipopolysaccharide. Cells and culture supernatants were subjected to extraction for metabolomic analysis with high-resolution LC-MS (HILIC and reverse phase -RP-chromatography in both negative and positive ionization modes) and GC-MS. The data were analyzed with R and the Worklow4Metabolomics and MetaboAnalyst online infrastructures. A total of 8,741 and 4,356 features were detected in the intracellular and extracellular content, respectively, after the filtering steps. Pathway analysis showed involvement of arachidonic acid metabolism, tryptophan metabolism and Krebs cycle in the response of LM to LPS, which was confirmed by the specific quantitation of selected compounds. This refined analysis highlighted a regulation of the kynurenin pathway as well as the serotonin biosynthesis pathway, and an involvement of aspartate-arginosuccinate shunt in the malate production. Macrophages M1 polarization is accompanied by changes in the cell metabolome, with the differential expression of metabolites involved in the promotion and regulation of inflammation and antimicrobial activity. The analysis of this macrophage immunometabolome may be of interest for the understanding of the pathophysiology of lung inflammatory disesases.

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Human lung and monocyte-derived macrophages differ with regard to the effects of β2-adrenoceptor agonists on cytokine release

Cited by 19 publications

References 57 publications

Bitter Taste Receptors (TAS2Rs) in Human Lung Macrophages: Receptor Expression and Inhibitory Effects of TAS2R Agonists

Bitter Taste Receptors (TAS2Rs) in Human Lung Macrophages: Receptor Expression and Inhibitory Effects of TAS2R Agonists

Adrenergic Signaling: A Targetable Checkpoint Limiting Development of the Antitumor Immune Response

Metabolic reprograming of LPS-stimulated human lung macrophages involves tryptophan metabolism and the aspartate-arginosuccinate shunt

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