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NLRP3 Inflammasome Mediates Dormant Neutrophil Recruitment following Sterile Lung Injury and Protects against Subsequent Bacterial Pneumonia in Mice.

ABSTRACT: Sterile lung injury is an important clinical problem that complicates the course of severely ill patients. Interruption of blood flow, namely ischemia-reperfusion (IR), initiates a sterile inflammatory response in the lung that is believed to be maladaptive. The rationale for this study was to elucidate the molecular basis for lung IR inflammation and whether it is maladaptive or beneficial. Using a mouse model of lung IR, we demonstrate that sequential blocking of inflammasomes [specifically, NOD-, LRR-, and pyrin domain-containing 3 (NLRP3)], inflammatory caspases, and interleukin (IL)-1?, all resulted in an attenuated inflammatory response. IL-1? production appeared to predominantly originate in conjunction with alveolar type 2 epithelial cells. Lung IR injury recruited unactivated or dormant neutrophils producing less reactive oxygen species thereby challenging the notion that recruited neutrophils are terminally activated. However, lung IR inflammation was able to limit or reduce the bacterial burden from subsequent experimentally induced pneumonia. Notably, inflammasome-deficient mice were unable to alter this bacterial burden following IR. Thus, we conclude that the NLRP3 inflammasome, through IL-1? production, regulates lung IR inflammation, which includes recruitment of dormant neutrophils. The sterile IR inflammatory response appears to serve an important function in inducing resistance to subsequent bacterial pneumonia and may constitute a critical part of early host responses to infection in trauma.

SUBMITTER: Tian X

PROVIDER: S-EPMC5671513 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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NLRP3 Inflammasome Mediates Dormant Neutrophil Recruitment following Sterile Lung Injury and Protects against Subsequent Bacterial Pneumonia in Mice.

Tian Xiaoli X Sun He H Casbon Amy-Jo AJ Lim Edward E Francis Kevin P KP Hellman Judith J Prakash Arun A

Frontiers in immunology 20171031

Sterile lung injury is an important clinical problem that complicates the course of severely ill patients. Interruption of blood flow, namely ischemia-reperfusion (IR), initiates a sterile inflammatory response in the lung that is believed to be maladaptive. The rationale for this study was to elucidate the molecular basis for lung IR inflammation and whether it is maladaptive or beneficial. Using a mouse model of lung IR, we demonstrate that sequential blocking of inflammasomes [specifically, N ...[more]

PMID: 29163464

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Project description:Intrauterine Listeria monocytogenes (L. monocytogenes) infections pose a major threat during pregnancy via affecting placental immune responses. However, the underlying mechanisms of placental defense against this pathogen remain ill-defined. Therefore, this study aims to investigate the function and the mechanism of inflammasomes on against L. monocytogenes infection during pregnancy. A listeriosis murine model and cell culture system was used to investigate the role of trophoblastic nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) in orchestrating innate immune responses to L. monocytogenes infection. Caspase-1 activity was determined using a caspase-1 activity colorimetric kit. NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC) in placental tissue was detected by immunohistochemistry. NLRP3 in HTR-8/SVneo cells was also detected by immunofluorescence. The expression of interleukin 1β (IL-1β), NLRP3, ASC, and caspase-1 was detected by Western blot. We characterized the NLRP3 inflammasome in trophoblast cells according to whether L. monocytogenes infection increased the activation of caspase-1 and the release of IL-1β. For human or mouse IL-1β in the culture supernatants and mouse tissue lysates were analyzed using ELISA Kits. Trophoblast cells constitutively expressed the components of the NLRP3 inflammasome. In vitro, L. monocytogenes triggers NLRP3 inflammasome activation in trophoblast cells by inducing caspase-1 activation, increasing the NLRP3 protein levels, IL-1β maturation and secretion in HTR-8/SVneo cells. In vivo, L. monocytogenes induces fetal resorption and IL-1β processing in pregnant mice. In addition, NLRP3-deficient mice were more prone to fetal loss than their wild-type counterparts following infection with L. monocytogenes at a lower infective dose. We conclude that trophoblast cells respond to L. monocytogenes infection through the NLRP3 receptor, resulting in inflammasome activation and IL-1β production, which prevents listeriosis during pregnancy.

Dataset Information

NLRP3 Inflammasome Mediates Dormant Neutrophil Recruitment following Sterile Lung Injury and Protects against Subsequent Bacterial Pneumonia in Mice.

Publications

NLRP3 Inflammasome Mediates Dormant Neutrophil Recruitment following Sterile Lung Injury and Protects against Subsequent Bacterial Pneumonia in Mice.

Similar Datasets

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