Glucose regulates hypoxia-induced NLRP3 inflammasome activation in macrophages.

Although the intimate linkage between hypoxia and inflammation is well known, the mechanism underlying this linkage has not been fully understood. Nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is an intracellular multiprotein complex that regulates interleukin-1β (IL-1β) secretion and pyroptosis, and is implicated in the pathogenesis of sterile inflammatory diseases. Here, we investigated the regulatory mechanism of NLRP3 inflammasome activation in response to hypoxia in macrophages. Severe hypoxia (0.1% O2 ) induced the processing of pro-IL-1β, pro-caspase-1, and gasdermin D, as well as the release of IL-1β and lactate dehydrogenase in lipopolysaccharide (LPS)-primed murine macrophages, indicating that hypoxia induces NLRP3 inflammasome-driven inflammation and pyroptosis. NLRP3 deficiency and a specific caspase-1 blockade inhibited hypoxia-induced IL-1β release. Hypoxia-induced IL-1β release and cell death were augmented under glucose deprivation, and an addition of glucose in the media negatively regulated hypoxia-induced IL-1β release. Under hypoxia and glucose deprivation, hypoxia-induced glycolysis was not driven and subsequently, the intracellular adenosine triphosphates (ATPs) were depleted. Atomic absorption spectrometry analysis showed a reduction of intracellular K+ concentrations, indicating the K+ efflux occurring under hypoxia and glucose deprivation. Furthermore, hypoxia and glucose deprivation-induced IL-1β release was significantly prevented by inhibition of K+ efflux and KATP channel blockers. In vivo experiments further revealed that IL-1β production was increased in LPS-primed mice exposed to hypoxia (9.5% O2 ), which was prevented by a deficiency of NLRP3, an apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1. Our results demonstrate that NLRP3 inflammasome can sense intracellular energy crisis as a danger signal induced by hypoxia and glucose deprivation, and provide new insights into the mechanism underlying hypoxia-induced inflammation.

Watanabe S ，Usui-Kawanishi F ，Karasawa T ，Kimura H ，Kamata R ，Komada T ，Inoue Y ，Mise N ，Kasahara T ，Takahashi M ... -  《-》

Heme oxygenase-1 dampens the macrophage sterile inflammasome response and regulates its components in the hypoxic lung.

Vitali SH ，Fernandez-Gonzalez A ，Nadkarni J ，Kwong A ，Rose C ，Mitsialis SA ，Kourembanas S ... -  《-》

Chalcones Display Anti-NLRP3 Inflammasome Activity in Macrophages through Inhibition of Both Priming and Activation Steps-Structure-Activity-Relationship and Mechanism Studies.

Leu WJ ，Chu JC ，Hsu JL ，Du CM ，Jiang YH ，Hsu LC ，Huang WJ ，Guh JH ... -  《MOLECULES》

Oxidized phosphatidylcholine induces the activation of NLRP3 inflammasome in macrophages.

The NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome is a multiprotein complex consisting of a receptor, an adaptor protein, and procaspase-1 that induces the secretion of the mature form of IL-1β in response to microbial infection and danger signals. Activation of the NLRP3 inflammasome induced by endogenous danger signal molecules is closely linked to the development and progress of chronic inflammatory diseases. The oxidation of phospholipids occurs upon cellular stress and damage, resulting in the accumulation of oxidized phosphatidylcholines (oxPAPC) such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-phosphocholine (POVPC) at inflammatory sites. In this study, we investigated whether oxidized phosphatidylcholine induces the activation of NLRP3 inflammasome in macrophages, leading to the secretion of IL-1β. POVPC induced the degradation of procaspase-1 to caspase-1(p10), the cleavage of pro-IL-1β to IL-1β, and oligomerization of ASC in primary mouse bone marrow-derived macrophages. POVPC-induced production of caspase-1, and IL-1β was abolished in macrophages derived from NLRP3- or caspase-1-deficient mice. In an air pouch model and a peritonitis model in mice, POVPC injection resulted in the production of caspase-1(p10), IL-1β, and IL-18 in wild-type, but not in NLRP3-deficient, mice. POVPC-induced inflammasome activation was mediated by mitochondrial reactive oxygen species resulting from intracellular Ca2+ signaling and mitochondrial destabilization. Our results demonstrate that endogenously produced oxidized phosphatidylcholines such as POVPC induce the activation of NLRP3 inflammasome, leading to the production of IL-1β in macrophages. The results provide an insight to understand how the oxidized lipids endogenously produced upon cellular stress and tissue damage contribute to the inflammatory reaction at pathologic sites.

Yeon SH ，Yang G ，Lee HE ，Lee JY ... -  《-》

Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner.

Conos SA ，Chen KW ，De Nardo D ，Hara H ，Whitehead L ，Núñez G ，Masters SL ，Murphy JM ，Schroder K ，Vaux DL ，Lawlor KE ，Lindqvist LM ，Vince JE ... -  《-》