NLRP3 inflammasome conjugates with mitochondria in LPS-induced acute lung injury

Background: NLRP3 inflammasome activation plays a critical role in various pulmonary inflammatory disorders. However, the conjugation of NLRP3 inflammasome with the mitochondria in acute lung injury is not well known. Methods: In this study, we aimed to evaluate the link between NLRP3 and mitochondria in various inflammatory cells using acute lung injury animal model and human plasma samples. Results: LPS-instilled mice showed typical features of neutrophil-dominant acute lung injury such as pulmonary neutrophilia, vascular leakage, nuclear translocation of nuclear factor-κB, increased expression of Toll-like receptor 4, and mitochondrial reactive oxygen species 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 mature IL-1β and IL-18, as well as mitochondrial proteins, were increased in the plasma from patients with acute lung injury. When LPS-instilled mice were treated with MCC950 or NecroX, mice showed the dramatic improvement of all inflammatory features, attenuation of NLRP3 inflammasome activation, and its dissociation from the mitochondrial fraction. Conclusion: These findings suggest that NLRP3 inflammasome assembly, especially the conjugation with mitochondria, plays a critical role in the pathogenesis of LPS-induced acute lung injury. Besides, this study provides a potential of the use of plasma NLRP3-related proteins or mitochondrial protein as a biomarker, which allows us to predict the severity and therapeutic responses for acute lung injury.