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Regulation of the NLRP3 inflammasome and macrophage pyroptosis by the p38 MAPK signaling pathway in a mouse model of acute lung injury.

ABSTRACT: Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) is characterized by uncontrolled progressive lung inflammation. Macrophages serve a key role in the pathogenesis of ALI/ARDS. Macrophage pyroptosis is a process of cell death releasing the proinflammatory cytokines interleukin (IL)?1? and IL?18. It was hypothesized that macrophage pyroptosis may partially account for the uncontrolled lung inflammation of ALI/ARDS. In the present study, greater macrophage pyroptosis in lipopolysaccharide (LPS)?treated macrophages and the ALI/ARDS mouse model was observed. The expression of nucleotide?binding domain, leucine?rich?containing family, pyrin domain?containing (NLRP)3 and IL?1? and cleavage of caspase?1 were significantly elevated following LPS treatment accompanied by greater activation of p38 mitogen?activated protein kinase (MAPK) signaling in vitro and in vivo. However, blocking p38 MAPK signaling through the inhibitor SB203580 significantly suppressed the acute lung injury and excessive lung inflammation in vivo, consistent with the reduced expression of the NLRP3 inflammasome and IL?1? and cleavage of caspase?1. Pretreatment of the rat NR8383 macrophage cell line with SB203580 significantly decreased the population of caspase?1+PI+ pyroptotic cells and expression of NLRP3/IL?1?. However, a larger population of Annexin V+PI? apoptotic cells was observed following blocking of the p38 MAPK signaling pathway. The results indicated that blockage of p38 MAPK signaling pathway skewed macrophage cell death from proinflammatory pyroptosis towards non?inflammatory apoptosis. These effects may contribute to attenuated acute lung injury and excessive inflammation in the SB203580?treated mice. The results may provide a novel therapeutic strategy for the treatment of uncontrolled lung inflammation in patients with ALI/ARDS.

SUBMITTER: Li D

PROVIDER: S-EPMC6172370 | biostudies-other | 2018 Aug

REPOSITORIES: biostudies-other

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Regulation of the NLRP3 inflammasome and macrophage pyroptosis by the p38 MAPK signaling pathway in a mouse model of acute lung injury.

Li Dandan D Ren Weiying W Jiang Zhilong Z Zhu Lei L

Molecular medicine reports 20180824 5

Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) is characterized by uncontrolled progressive lung inflammation. Macrophages serve a key role in the pathogenesis of ALI/ARDS. Macrophage pyroptosis is a process of cell death releasing the proinflammatory cytokines interleukin (IL)‑1β and IL‑18. It was hypothesized that macrophage pyroptosis may partially account for the uncontrolled lung inflammation of ALI/ARDS. In the present study, greater macrophage pyroptosis in lipopolys ...[more]

PMID: 30152849

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Project description:Propofol infusion syndrome (PRIS) is an uncommon life-threatening complication observed most often in patients receiving high-dose propofol. High-dose propofol treatment with a prolonged duration can damage the immune system. However, the associated molecular mechanisms remain unclear. An increasing number of clinical and experimental observations have demonstrated that tissue-resident macrophages play a critical role in immune regulation during anaesthesia and procedural sedation. Since the inflammatory response is essential for mediating propofol-induced cell death and proinflammatory reactions, we hypothesised that propofol overdose induces macrophage pyroptosis through inflammasomes. Using primary cultured bone marrow-derived macrophages, murine macrophage cell lines (RAW264.7, RAW-asc and J774) and a mouse model, we investigated the role of NLRP3 inflammasome activation and secondary pyroptosis in propofol-induced cell death. We found that high-dose propofol strongly cleaved caspase-1 but not caspase-11 and biosynthesis of downstream interleukin (IL)-1β and IL-18. Inhibition of caspase-1 activity blocks IL-1β production. Moreover, NLRP3 deletion moderately suppressed cleaved caspase-1 as well as the proportion of pyroptosis, while levels of AIM2 were increased, triggering a compensatory pathway to pyroptosis in NLRP3-/- macrophages. Here, we show that propofol-induced mitochondrial reactive oxygen species (ROS) can trigger NLRP3 inflammasome activation. Furthermore, apoptosis-associated speck-like protein (ASC) was found to mediate NLRP3 and AIM2 signalling and contribute to propofol-induced macrophage pyroptosis. In addition, our work shows that propofol-induced apoptotic initiator caspase (caspase-9) subsequently cleaved effector caspases (caspase-3 and 7), indicating that both apoptotic and pyroptotic cellular death pathways are activated after propofol exposure. Our studies suggest, for the first time, that propofol-induced pyroptosis might be restricted to macrophage through an NLRP3/ASC/caspase-1 pathway, which provides potential targets for limiting adverse reactions during propofol application. These findings demonstrate that propofol overdose can trigger cell death through caspase-1 activation and offer new insights into the use of anaesthetic drugs.

Dataset Information

Regulation of the NLRP3 inflammasome and macrophage pyroptosis by the p38 MAPK signaling pathway in a mouse model of acute lung injury.

Publications

Regulation of the NLRP3 inflammasome and macrophage pyroptosis by the p38 MAPK signaling pathway in a mouse model of acute lung injury.

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