Autophagy alleviates mitochondrial DAMP-induced acute lung injury by inhibiting NLRP3 inflammasome.
AIM
Acute lung injury (ALI) is characterized by alveolar macrophage overactivation and uncontrolled pulmonary inflammation. Mitochondrial damage-associated molecular patterns (MTDs), one type of damage-associated molecular patterns (DAMPs) released from ruptured mitochondrial, can induce inflammation which participates in the pathogenesis of ALI. Despite the critical role of autophagy in inflammatory response, little is known about its function in MTDs-induced ALI. Herein we have studied how autophagy attenuates MTDs-induced ALI in vitro and in vivo.


MAIN METHODS
Exogenous MTDs were injected into mice through tail vein injection or directly treated with cultured alveolar macrophage cell lines to construct MTDs-induced ALI models. Rapamycin and 3-MA were used to regulate autophagy in vivo and in vitro. The expressions of Caspase-1, IL-1β, and their precursor were measured. Inhibition the activation of NLRP3 inflammasome to discover the candidate targets and potential molecular pathways involved in autophagy mitigating the MTDs-induced ALI.


KEY FINDINGS
After treatment with MTDs the expression levels of inflammatory cytokines and NLRP3 inflammasome-associated proteins were gradually increased in vitro and in vivo. Most importantly, with autophagy enhanced by rapamycin, all the secretion of inflammation cytokine, the level of lung injury, and the expression level of NLRP3 inflammasome-associated proteins were greatly decreased in MTDs-induced mouse model. MTDs-induced inflammation and lung injury were alleviated by autophagy enhancement. Autophagy can function as an effective way to alleviate inflammation in MTDs-induced ALI by inhibiting NLRP3 inflammasome and may represent a therapeutic target in modulating MTDs-induced inflammatory response.
['Peng|Wei|W|', 'Peng|Fei|F|', 'Lou|Yuanlei|Y|', 'Li|Yong|Y|', 'Zhao|Ning|N|', 'Shao|Qiang|Q|', 'Chen|Jiaquan|J|', 'Qian|Kejian|K|', 'Zeng|Zhenguo|Z|', 'Zhan|Yian|Y|', 'Jiang|Rong|R|', 'Liu|Fen|F|']
D055371:Acute Lung Injury D000225:Adenine D000067531:Alarmins D000818:Animals D001343:Autophagy D016207:Cytokines D004195:Disease Models, Animal D058847:Inflammasomes D016676:Macrophages, Alveolar D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D008928:Mitochondria D000071199:NLR Family, Pyrin Domain-Containing 3 Protein D011014:Pneumonia D020123:Sirolimus
Autophagy NLRP3 inflammasome Acute lung injury (ALI) Mitochondrial damage-associated molecular patterns (MTDs) Damage-associated molecular patterns (DAMPs)