The NLRP3 inflammasome modulates glycolysis by increasing PFKFB3 in an IL-1β-dependent manner in macrophages

Abstract

Inflammation and metabolism are intricately linked during inflammatory diseases in which activation of the nucleotide-binding domain–like receptors Family Pyrin Domain Containing 3 (NLRP3) inflammasome, an innate immune sensor, is critical. Several factors can activate the NLRP3 inflammasome, but the nature of the link between NLRP3 inflammasome activation and metabolism remains to be thoroughly explored. This study investigates whether the small molecule inhibitor of the NLRP3 inflammasome, MCC950, modulates the lipopolysaccharide (LPS) -and amyloid-β (Aβ)-induced metabolic phenotype and inflammatory signature in macrophages. LPS + Aβ induced IL-1β secretion, while pre-treatment with MCC950 inhibited this. LPS + Aβ also upregulated IL-1β mRNA and supernatant concentrations of TNFα, IL-6 and IL-10, however these changes were insensitive to MCC950, confirming that MCC950 specifically targets inflammasome activation in BMDMs. LPS + Aβ increased glycolysis and the glycolytic enzyme, PFKFB3, and these effects were decreased by MCC950. These findings suggest that NLRP3 inflammasome activation may play a role in modulating glycolysis. To investigate this further, the effect of IL-1β on glycolysis was assessed. IL-1β stimulated glycolysis and PFKFB3, mimicking the effect of LPS + Aβ and adding to the evidence that inflammasome activation impacts on metabolism. This contention was supported by the finding that the LPS + Aβ-induced changes in glycolysis and PFKFB3 were attenuated in BMDMs from NLRP3-deficient and IL-1R1-deficient mice. Consistent with a key role for PFKFB3 is the finding that the PFKFB3 inhibitor, 3PO, attenuated the LPS + Aβ-induced glycolysis. The data demonstrate that activation of the NLRP3 inflammasome, and the subsequent release of IL-1β, play a key role in modulating glycolysis via PFKFB3. Reinstating metabolic homeostasis by targeting the NLRP3 inflammasome-PFKFB3 axis may provide a novel therapeutic target for treatment of acute and chronic disease.

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia

“…We identified aberrant responses following exposure to classical pro‐inflammatory stimuli (LPS/IFNγ) in TREM2 hypomorphic iPS‐Mg; specifically, reduced morphological changes and TNFα release. Both responses require rapid energy production which is produced when microglia undergo the metabolic switch to glycolysis . Glycolysis allows energy production and uptake of essential nutrients to support the rapid changes required by “activated” microglia in response to a stimulus, such as phagocytosis, proliferation, migration, and induction of protein synthesis for cytokine and chemokine secretion .…”

Cigarette smoke inhibits the NLRP3 inflammasome and leads to caspase‐1 activation via the TLR4‐TRIF‐caspase‐8 axis in human macrophages

“…33 Furthermore, we have found that the classical substrates of caspase-1, that is, IL-1β and IL-18, were strongly reduced in CSE-treated macrophages. 46,49 As an adaptive response during infection, activation of caspase-1 reduces the cellular glycolytic rate by promoting the cleavage of glycolytic enzymes. Optimal activation of macrophages is sustained by the increase of the glycolytic flux that generates, among others, a positive crosstalk between glycolysis and the NLRP3 inflammasome that is required for proper response to infections.…”

Aminooxyacetic acid attenuates post‐infarct cardiac dysfunction by balancing macrophage polarization through modulating macrophage metabolism in mice

“…Further, studies proved that NLRP3 inflammasome is predominantly activated in macrophages and up‐regulated in M1 macrophages but down‐regulated in M2 . What is more, the inhibition of NLRP3 impeded glycolysis and induced a macrophage phenotype transformation from pro‐inflammatory to anti‐inflammatory . Therefore, we investigated the effect of AOAA on NLRP3‐Caspase1/IL‐1β signalling pathway by Western blotting and qPCR analysis.…”