Activation of NLRP3 Inflammasome in Alveolar Macrophages Contributes to Mechanical Stretch-Induced Lung Inflammation and Injury

Abstract

Mechanical ventilation of lungs is capable of activating the innate immune system and inducing sterile inflammatory response. The proinflammatory cytokine IL-1β is among the definitive markers for accurately identifying ventilator-induced lung inflammation. However, mechanisms of IL-1β release during mechanical ventilation are unknown. Here we show that cyclic stretch activates the NLRP3 inflammasomes and induces the release of IL-1β in mouse alveolar macrophages via caspase-1- and TLR4-dependent mechanisms. We also observed that NADPH oxidase subunit gp91phox was dispensable for stretch-induced cytokine production whereas mitochondrial generation of reactive oxygen species was required for stretch-induced NLRP3 inflammasome activation and IL-1β release. Further, mechanical ventilation activated the NLRP3 inflammasomes in mouse alveolar macrophages and increased the production of IL-1β in vivo. IL-1β neutralization significantly reduced mechanical ventilation-induced inflammatory lung injury. These findings suggest that the alveolar macrophage NLRP3 inflammasome may sense lung alveolar stretch to induce the release of IL-1β, and hence may contribute to the mechanism of lung inflammatory injuryduring mechanical ventilation.

Mitochondrial CaMKII inhibition in airway epithelium protects against allergic asthma

“…Both NF-κB activation and Mt-ROS generation have been implicated in the activation of NLRP3 inflammasomes (16,35,47,65,74,75), with emerging data suggesting a role for inflammasomes in a variety of lung diseases (16,31,(44)(45)(46)(76)(77)(78). In a model of house dust mite-induced asthma, airway epithelial NLRP3 expression correlates with enhanced asthma phenotypes, which can be reduced by scavenging Mt-ROS (16).…”

Mitochondria in lung disease

“…Activation of NLRP3 signaling, a key regulator of IL-1β and IL-18 secretion, is regulated by mitochondrial pathways (84,112), and the NLRP3 inflammasome adaptor (ASC) and UCP2 regulate hypoxia-induced PH in mice (51,113,114). NLRP3 inflammasome activation by mROS in bronchial epithelial cells is required for allergic inflammation (104) and in AMs contributes to mechanical stretch-induced lung inflammation and injury (115). Caspase-1-dependent IL-1β secretion is critical for host defence against Chlamydia pneumoniae lung infection (116), and mitochondrial Ca…”

Autophagy in pulmonary macrophages mediates lung inflammatory injury via NLRP3 inflammasome activation during mechanical ventilation

“…A well-established in vivo mouse model of VILI was utilized as described previously (12,19,40). Briefly, mice were anesthetized with an intraperitoneal injection of a ketamine/xylazine mixture (75 mg/kg) and inhalation of 1% isoflurane for maintenance.…”

“…Mouse AMs were depleted as previously described (40). Briefly, clodronate liposomes were made with phosphatidylserine, phosphatidylcholine, and cholesterol at a molar ratio of 1:6:4 in chloroform.…”