Xanthine oxidoreductase regulates macrophage IL1β secretion upon NLRP3 inflammasome activation.
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ABSTRACT:
SUBMITTER: Ives A
PROVIDER: S-EPMC4382995 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome is triggered by various stimuli. Whether the NLRP3 inflammasome is activated during the monocyte clearing of aged or damaged erythrocytes is unknown. This work aimed to determine whether the NLRP3 inflammasome is activated during the THP-1 cell engulfing of aged erythrocytes. In the study, THP-1 cells were treated with PMA and then coincubated with untreated red blood cells (RBCs), 42 °C-treated RBCs, immunoglobulin G (IgG) anti-D-sensitized RBCs, Rhnull/Rhmod RBC sample, hemoglobin, and RBC ghost. The activation of the NLRP3 inflammasome and production of some proinflammatory cytokines were determined using immunoblotting, cytometric bead array, and digital PCR. An NLRP3 inflammasome inhibitor was also used to evaluate the alteration of the NLRP3 activation and RBC clearance rate. The untreated RBCs, 42 °C-incubated RBCs, IgG-opsonized RBCs, Rhnull/Rhmod RBCs, RBC ghosts, and hemoglobin induced the THP-1-cell-mediated activation of the NLRP3 inflammasome and the production of inflammatory cytokines. The RBC clearance rate exhibited a positive correlation with the expression of proinflammatory cytokines. The NLRP3 inflammasome inhibitor reduced the NLRP3 activation and RBC phagocytosis rate. The NLRP3 inflammasome was activated during the clearance of the aged erythrocytes through unopsonized and opsonized pathways. However, the mechanism of such phenomenon needs to be further elucidated. Such mechanism may provide new insight into the assessment of the safety of transfusing long-storage RBC based on cytokine levels.
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Project description:Background and purposeThere are no medications currently available to treat metabolic inflammation. Bruton's tyrosine kinase (BTK) is highly expressed in monocytes and macrophages and regulates NF-κB and NLRP3 inflammasome activity; both propagate metabolic inflammation in diet-induced obesity.Experimental approachUsing an in vivo model of chronic inflammation, high-fat diet (HFD) feeding, in male C57BL/6J mice and in vitro assays in primary murine and human macrophages, we investigated if ibrutinib, an FDA approved BTK inhibitor, may represent a novel anti-inflammatory medication to treat metabolic inflammation.Key resultsHFD-feeding was associated with increased BTK expression and activation, which was significantly correlated with monocyte/macrophage accumulation in the liver, adipose tissue, and kidney. Ibrutinib treatment to HFD-fed mice inhibited the activation of BTK and reduced monocyte/macrophage recruitment to the liver, adipose tissue, and kidney. Ibrutinib treatment to HFD-fed mice decreased the activation of NF-κB and the NLRP3 inflammasome. As a result, ibrutinib treated mice fed HFD had improved glycaemic control through restored signalling by the IRS-1/Akt/GSK-3β pathway, protecting mice against the development of hepatosteatosis and proteinuria. We show that BTK regulates NF-κB and the NLRP3 inflammasome specifically in primary murine and human macrophages, the in vivo cellular target of ibrutinib.Conclusion and implicationsWe provide "proof of concept" evidence that BTK is a novel therapeutic target for the treatment of diet-induced metabolic inflammation and ibrutinib may be a candidate for drug repurposing as an anti-inflammatory agent for the treatment of metabolic inflammation in T2D and microvascular disease.
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Project description:Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne virus that causes hemorrhagic fever. Previous studies showed that SFTSV-infected patients exhibited elevated levels of pro-inflammatory cytokines like interleukin-1β (IL-1β), indicating that SFTSV infection may activate inflammasomes. However, the detailed mechanism remains poorly understood. Herein, we found that SFTSV could stimulate the IL-1β secretion in the infected human peripheral blood mononuclear cells (PBMCs), human macrophages, and C57/BL6 mice. We demonstrate that the maturation and secretion of IL-1β during SFTSV infection is mediated by the nucleotide and oligomerization domain, leucine-rich repeat-containing protein family, pyrin-containing domain 3 (NLRP3) inflammasome. This process is dependent on protease caspase-1, a component of the NLRP3 inflammasome complex. For the first time, our study discovered the role of NLRP3 in response to SFTSV infection. This finding may lead to the development of novel drugs to impede the pathogenesis of SFTSV infection.
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