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 comp...

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Published in:Journal of cellular physiology 2020-10, Vol.235 (10), p.7554-7566
Main Authors: Watanabe, Sachiko, Usui‐Kawanishi, Fumitake, Karasawa, Tadayoshi, Kimura, Hiroaki, Kamata, Ryo, Komada, Takanori, Inoue, Yoshiyuki, Mise, Nathan, Kasahara, Tadashi, Takahashi, Masafumi
Format: Article
Language:English
Subjects:
Adenosine
Adenosine triphosphate
Adenosine Triphosphate - metabolism
Animals
Apoptosis
Apoptosis - drug effects
Atomic absorption analysis
Atomic absorption spectroscopy
Caspase
Caspase 1 - metabolism
Cell activation
Cell death
Cell Death - drug effects
Cells, Cultured
Deprivation
Efflux
Glucose
Glucose - metabolism
Glycolysis
Hypoxia
Hypoxia - metabolism
Inflammasomes
Inflammasomes - metabolism
Inflammation
Inflammation - metabolism
Inflammatory diseases
Interleukin-1beta - metabolism
Interleukins
interleukin‐1
Intracellular
L-Lactate dehydrogenase
Lactate dehydrogenase
Lactic acid
Lipopolysaccharides
Lipopolysaccharides - pharmacology
Macrophages
Macrophages - drug effects
Macrophages - metabolism
Male
Mice
Mice, Inbred C57BL
NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
Nucleotides
Oligomerization
Pathogenesis
Potassium
Potassium - metabolism
potassium efflux
Pyrin protein
Pyroptosis
Regulatory mechanisms (biology)
Signal Transduction - drug effects
Signal Transduction - physiology
Spectral analysis
Spectrometry
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Summary: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. Hypoxia induces nucleotide‐binding oligomerization domain‐like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome activation, resulting in subsequent interleukin‐1β release and pyroptotic cell death in macrophages. Hypoxia‐induced NLRP3 inflammasome activation is markedly influenced by glucose levels.
ISSN:0021-9541
1097-4652
DOI:10.1002/jcp.29659