Mitochondria-associated NLRP3 inflammasome contributes to LPS-induced neutrophil-dominant acute lung injury = Mitochondria-associated NLRP3 inflammasome contributes to LPS-induced neutrophil-dominant acute lung injury

다국어 초록 (Multilingual Abstract)

Purpose: NLRP3 inflammasome activation has been demonstrated to play a critical role in various pulmonary inflammatory disorders including acute lung injury/acute respiratory distress syndrome. Besides, mitochondrial reactive oxygen species (ROS) induce the assembly of the NLRP3 inflammasome. Some NLRP family members are known to localize to the mitochondria. However, the localization and the role of NLRP3 in the mitochondrial fraction are not well known. Methods: In this study, we aimed to evaluate the localization of NLRP3 in mitochondria of various inflammatory cells under LPS-induced neutrophilic pulmonary inflammation and pharmacologic effects of MCC950, a specific NLRP3 inflammasome inhibitor on LPS-induced acute lung injury using animal models and human samples. Results: LPS-instilled mice showed typical features of neutrophil-dominant acute lung injury; pulmonary neutrophilia, vascular leakage, nuclear translocation of nuclear factor-κB (NF-κB), increased expression of Toll-like receptor 4 (TLR4), and mitochondrial ROS generation. Interestingly, the NLRP3 inflammasome activation indicators, NLRP3, caspase-1, IL-1β, and IL-18 were dramatically increased in lung tissues, particularly in the mitochondrial fraction. Moreover, we also found that NLRP3 inflammasome effector cytokines; mature IL-1β and IL-18 as well as mitochondria fractions were increased in the plasma from patients with neutrophilic acute lung injury. When MCC950 or NecroX was administered to LPS-instilled mice, mice showed the dramatic improvement of all inflammatory features including NLRP3 inflammasome activation, particularly in the mitochondrial fraction-associated ones. Conclusion: These findings suggest that NLRP3 inflammasome assembly, especially mitochondrial-associated NLRP3 plays critical roles in the pathogenesis of LPS-induced pulmonary inflammation and that plasma NLRP3-related proteins or mitochondrial volume can be a biomarker predicting the severity and therapeutic responses of the inflammasome inhibitors in neutrophilic acute lung injury.