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NLRP3/Caspase-1 inflammasome activation is decreased in alveolar macrophages in patients with lung cancer.

ABSTRACT: Lung cancer (LC) remains the leading cause of cancer-related mortality. The interaction of cancer cells with their microenvironment, results in tumor escape or elimination. Alveolar macrophages (AMs) play a significant role in lung immunoregulation, however their role in LC has been outshined by the study of tumor associated macrophages. Inflammasomes are key components of innate immune responses and can exert either tumor-suppressive or oncogenic functions, while their role in lung cancer is largely unknown. We thus investigated the NLRP3 pathway in Bronchoalveolar Lavage derived alveolar macrophages and peripheral blood leukocytes from patients with primary lung cancer and healthy individuals. IL-1β and IL-18 secretion was significantly higher in unstimulated peripheral blood leukocytes from LC patients, while IL-1β secretion could be further increased upon NLRP3 stimulation. In contrast, in LC AMs, we observed a different profile of IL-1β secretion, characterized mainly by the impairment of IL-1β production in NLRP3 stimulated cells. AMs also exhibited an impaired TLR4/LPS pathway as shown by the reduced induction of IL-6 and TNF-α. Our results support the hypothesis of tumour induced immunosuppression in the lung microenvironment and may provide novel targets for cancer immunotherapy.

SUBMITTER: Lasithiotaki I

PROVIDER: S-EPMC6203254 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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NLRP3/Caspase-1 inflammasome activation is decreased in alveolar macrophages in patients with lung cancer.

Lasithiotaki Ismini I Tsitoura Eliza E Samara Katerina D KD Trachalaki Athina A Charalambous Irini I Tzanakis Nikolaos N Antoniou Katerina M KM

PloS one 20181026 10

Lung cancer (LC) remains the leading cause of cancer-related mortality. The interaction of cancer cells with their microenvironment, results in tumor escape or elimination. Alveolar macrophages (AMs) play a significant role in lung immunoregulation, however their role in LC has been outshined by the study of tumor associated macrophages. Inflammasomes are key components of innate immune responses and can exert either tumor-suppressive or oncogenic functions, while their role in lung cancer is la ...[more]

PMID: 30365491

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Project description:For more than 3 decades, mounting evidence has associated porcine reproductive and respiratory syndrome virus (PRRSV) infection with late-term abortions and stillbirths in sows and respiratory disease in piglets, causing enormous economic losses to the global swine industry. However, to date, the underlying mechanisms of PRRSV-triggered cell death have not been well clarified, especially in the pulmonary inflammatory injury characterized by the massive release of pro-inflammatory factors. Here, we demonstrated that PRRSV infection triggered gasdermin D-mediated host pyroptosis in vitro and in vivo. Mechanistically, PRRSV infection triggered disassembly of the trans-Golgi network (TGN); the dispersed TGN then acted as a scaffold for NLRP3 activation through phosphatidylinositol-4-phosphate. In addition, PRRSV replication-transcription complex (RTC) formation stimulated TGN dispersion and pyroptotic cell death. Furthermore, our results indicated that TMEM41B, an endoplasmic reticulum (ER)-resident host protein, functioned as a crucial host factor in the formation of PRRSV RTC, which is surrounded by the intermediate filament network. Collectively, these findings uncover new insights into clinical features as previously unrecognized mechanisms for PRRSV-induced pathological effects, which may be conducive to providing treatment options for PRRSV-associated diseases and may be conserved during infection by other highly pathogenic viruses. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the pathogens responsible for major economic losses in the global swine industry. Characterizing the detailed process by which PRRSV induces cell death pathways will help us better understand viral pathogenesis and provide implications for therapeutic intervention against PRRSV. Here, we showed that PRRSV infection induces GSDMD-driven host pyroptosis and IL-1β secretion through NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in vitro and in vivo. Furthermore, the molecular mechanisms of PRRSV-induced NLRP3 inflammasome activation and pyroptosis are elucidated here. The dispersed trans-Golgi network (TGN) induced by PRRSV serves as a scaffold for NLRP3 aggregation into multiple puncta via phosphatidylinositol 4-phosphate (PtdIns4P). Moreover, the formation of PRRSV replication-transcription complex is essential for TGN dispersion and host pyroptosis. This research advances our understanding of the PRRSV-mediated inflammatory response and cell death pathways, paving the way for the development of effective treatments for PRRSV diseases.

Project description:BackgroundEpidemiological studies have demonstrated that individuals with preexisting conditions, including diabetes mellitus (DM), are more susceptible to air pollution. However, the underlying mechanisms remain unclear. In this study, we proposed that a high glucose setting enhances ambient fine particulate matter (PM2.5)-induced macrophage activation and secretion of the proinflammatory cytokine, IL-1β, through activation of the NLRP3 inflammasome, altering the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs).ResultsExposure of mouse alveolar macrophages to non-cytotoxic doses of PM2.5 led to upregulation of IL-1β, activation of the NLRP3 inflammasome, increased nuclear translocation of the transcription factor NF-κB, increased generation of reactive oxygen species (ROS), and increased expression and enzymatic activity of MMP-9; these effects were enhanced when cells were pretreated with high glucose. However, pretreatment in a high glucose setting alone did not induce significant changes. ROS generation following PM2.5 exposure was abolished when cells were pretreated with ROS scavengers such as Trolox and superoxide dismutase (SOD), or with an NADPH oxidase inhibitor, DPI. Pretreatment of cells with DPI attenuated the effects of a high glucose setting on PM2.5-induced upregulation of IL-1β, activation of the NLRP3 inflammasome, and nuclear translocation of NF-κB. In addition, enhancement of PM2.5-induced expression and enzymatic activity of MMP-9 following high glucose pretreatment was not observed in primary alveolar macrophages obtained from NLRP3 or IL-1R1 knockout (KO) mice, where pro-IL-1β cannot be cleaved to IL-1β or cells are insensitive to IL-1β, respectively.ConclusionsThis study demonstrated that exposure of mouse alveolar macrophages to PM2.5 in a high glucose setting enhanced PM2.5-induced production of IL-1β through activation of the NLRP3 inflammasome and nuclear translocation of NF-κB due to PM2.5-induced oxidative stress, leading to MMP-9 upregulation. The key role of NADPH oxidase in PM2.5-induced ROS generation and activation of the IL-1β secretion pathway and the importance of IL-1β secretion and signaling in PM2.5-induced increases in MMP-9 enzymatic activity were also demonstrated. This study provides a further understanding of the potential mechanisms underlying the susceptibility of individuals with DM to air pollution and suggests potential therapeutic targets.

Dataset Information

NLRP3/Caspase-1 inflammasome activation is decreased in alveolar macrophages in patients with lung cancer.

Publications

NLRP3/Caspase-1 inflammasome activation is decreased in alveolar macrophages in patients with lung cancer.

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