NLRP3 Inflammasome Modulates Post-Burn Lipolysis and Hepatic Fat Infiltration via Fatty Acid Synthase.
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ABSTRACT:
SUBMITTER: Vinaik R
PROVIDER: S-EPMC6185951 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cellular lipid metabolism has been linked to immune responses; however, the precise mechanisms by which de novo fatty acid synthesis can regulate inflammatory responses remain unclear. The NLRP3 inflammasome serves as a platform for caspase-1-dependent maturation and secretion of proinflammatory cytokines. Here, we demonstrated that the mitochondrial uncoupling protein-2 (UCP2) regulates NLRP3-mediated caspase-1 activation through the stimulation of lipid synthesis in macrophages. UCP2-deficient mice displayed improved survival in a mouse model of polymicrobial sepsis. Moreover, UCP2 expression was increased in human sepsis. Consistently, UCP2-deficient mice displayed impaired lipid synthesis and decreased production of IL-1? and IL-18 in response to LPS challenge. In macrophages, UCP2 deficiency suppressed NLRP3-mediated caspase-1 activation and NLRP3 expression associated with inhibition of lipid synthesis. In UCP2-deficient macrophages, inhibition of lipid synthesis resulted from the downregulation of fatty acid synthase (FASN), a key regulator of fatty acid synthesis. FASN inhibition by shRNA and treatment with the chemical inhibitors C75 and cerulenin suppressed NLRP3-mediated caspase-1 activation and inhibited NLRP3 and pro-IL-1? gene expression in macrophages. In conclusion, our results suggest that UCP2 regulates the NLRP3 inflammasome by inducing the lipid synthesis pathway in macrophages. These results identify UCP2 as a potential therapeutic target in inflammatory diseases such as sepsis.
| S-EPMC4319445 | biostudies-literature
Project description:Background/objectivesPrevious research has shown maternal betaine supplementation alleviates fetal-derived hepatic steatosis. Therefore, this study examined the anti-inflammatory effect of maternal betaine intake in offspring mice and its mechanism.Materials/methodsFemale C57BL/6J mice and their offspring were randomly divided into 3 groups according to the treatment received during gestation and lactation: control diet (CD), fatty liver disease (FLD), and fatty liver disease + 1% betaine (FLD-BET). The FLD group was given a high-fat diet and streptozotocin (HFD + STZ), and the FLD-BET group was treated with HFD + STZ + 1% betaine. After weaning, the offspring mice were given a normal diet for 5 weeks and then dissected to measure the relevant indexes.ResultsCompared to the CD group, the offspring mice in the FLD group revealed obvious hepatic steatosis and increased serum levels of alanine aminotransferase, interleukin (IL)-6, and tumor necrosis factor (TNF)-α; maternal betaine supplementation reversed these changes. The hepatic mRNA expression levels of IL-6, IL-18, and Caspase-1 were significantly higher in the FLD group than in the CD group. Maternal betaine supplementation reduced the expression of IL-1β, IL-6, IL-18, and apoptosis-associated speck-like protein containing C-terminal caspase recruitment domain (ASC). Maternal betaine supplementation also reversed the increasing protein expressions of nitric oxide dioxygenase-like receptor family pyrin domain containing 3 (NLRP3), ASC, Caspase-1, IL-1β, and IL-18 in offspring mice exposed to HFD + STZ. Maternal betaine supplementation decreased the homocysteine (Hcy) and s-adenosine homocysteine (SAH) levels significantly in the livers. Furthermore, the hepatic Hcy concentrations showed significant inverse relationships with the mRNA expression of TNF-α, NLRP3, ASC, and IL-18. The hepatic SAH concentration was inversely associated with the IL-1β mRNA expression.ConclusionsThe lipotropic and anti-inflammatory effect of maternal betaine supplementation may be associated with the inhibition of NLRP3 inflammasome in the livers of the offspring mice.
| S-EPMC10694418 | biostudies-literature
Project description:The NLRP3 inflammasome responds to infection and tissue damage, and rapidly escalates the intensity of inflammation by activating interleukin (IL)-1?, IL-18 and cell death by pyroptosis. How the NLRP3 inflammasome is negatively regulated is poorly understood. Here we show that NLRP3 inflammasome activation is suppressed by sumoylation. NLRP3 is sumoylated by the SUMO E3-ligase MAPL, and stimulation-dependent NLRP3 desumoylation by the SUMO-specific proteases SENP6 and SENP7 promotes NLRP3 activation. Defective NLRP3 sumoylation, either by NLRP3 mutation of SUMO acceptor lysines or depletion of MAPL, results in enhanced caspase-1 activation and IL-1? release. Conversely, depletion of SENP7 suppresses NLRP3-dependent ASC oligomerisation, caspase-1 activation and IL-1? release. These data indicate that sumoylation of NLRP3 restrains inflammasome activation, and identify SUMO proteases as potential drug targets for the treatment of inflammatory diseases.
| S-EPMC6070540 | biostudies-literature
Project description:Increasing evidence indicates that prolonged fat-rich diet (HFD) ingestion is a predisposing factor for metabolic disorder-associated system inflammation and oxidative stress injury, which contributes to the occurrence of non-alcoholic fatty liver disease (NAFLD). NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-mediated inflammatory infiltration was determined to participate in NAFLD. X-linked inhibitor of apoptosis protein (XIAP) was recently confirmed as an essential regulator for apoptosis in cells. However, the role of XIAP in HFD-induced NAFLD is still not understood. Here, XIAP was characterized with respect to HFD-induced NLRP3 inflammasome activation and reactive oxygen species (ROS) generation in vivo and palmitate (PA)-treated cells in vitro. After HFD administration, hepatic injury was confirmed via histological assessment (grading and staging of NAFLD) and biochemical parameters, oxidative stress, and reduced antioxidant activity. Up-regulated hepatic dysfunction were further indicated by elevated dyslipidemia, lipid accumulation, and decreased fatty acid β-oxidation associated gene expression. Moreover, in the absence of XIAP, NLRP3 signaling activated by HFD-triggered oxidative stress was up-regulated, accompanied by reduction in antioxidants including HO-1, NQO-1, GST, SOD and Nrf2 activity. The detrimental effects of XIAP blocking on hepatic steatosis and related pathologies were also confirmed in PA-treated mouse liver cells. In contrast, overexpression of XIAP by transfection in vitro restrained PA-stimulated hepatic steatosis by suppression of oxidative stress, NLRP3 related inflammatory response, and impairment of Nrf2 activity, further alleviating abnormal metabolic disorder associated NAFLD. Taken together, the present study helped to elucidate how HFD-induced hepatic steatosis was regulated by XIAP, possibly via the inhibition of NLRP3 signaling and oxidative stress injury.
| S-EPMC6949096 | biostudies-literature
Project description:AimsImpairment in adenosine monophosphate-activated protein kinase (AMPK) activity and NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation are associated with several metabolic and inflammatory diseases. In this study, we investigated the role of AMPK/NLRP3 inflammasome axis in the molecular mechanism underlying pain perception.ResultsImpairment in AMPK activation induced by compound C or sunitinib, two AMPK inhibitors, provoked hyperalgesia in mice (p<0.001) associated with marked NLRP3 inflammasome protein activation and increased serum levels of interleukin-1β (IL-1β) (24.56±0.82 pg/ml) and IL-18 (23.83±1.882 pg/ml) compared with vehicle groups (IL-1β: 8.15±0.44; IL-18: 4.92±0.4). This effect was rescued by increasing AMPK phosphorylation via metformin treatment (p<0.001), caloric restriction diet (p<0.001), or NLRP3 inflammasome genetic inactivation using NLRP3 knockout (nlrp3(-/-)) mice (p<0.001). Deficient AMPK activation and overactivation of NLRP3 inflammasome axis were also observed in blood cells from patients with fibromyalgia (FM), a prevalent human chronic pain disease. In addition, metformin treatment (200 mg/daily), which increased AMPK activation, restored all biochemical alterations examined by us in blood cells and significantly improved clinical symptoms, such as, pain, fatigue, depression, disturbed sleep, and tender points, in patients with FM.Innovation and conclusionsThese data suggest that AMPK/NLRP3 inflammasome axis participates in chronic pain and that NLRP3 inflammasome inhibition by AMPK modulation may be a novel therapeutic target to fight against chronic pain and inflammatory diseases as FM.
| S-EPMC4742979 | biostudies-literature
Project description:Sepsis/endotoxemia activates the NLRP3 inflammasome of macrophages leading to the maturation and release of IL-1β, an important mediator of the inflammatory response. Reactive oxygen species have been implicated in NLRP3 inflammasome activation. Further, our preliminary studies indicated that LPS challenge of cardiac fibroblasts could phosphorylate protein kinase R (PKR) on threonine 451 and increase message for pro-IL-1 β. Thus, the major aim of the present study was to address the role of PKR and the oxidant, peroxynitrite, in the two-tiered function of the NLRP3 inflammasome (priming and activation). Materials and Methods: Isolated murine fibroblasts were primed with LPS (1 μg/ml) for 6 h and subsequently activated by an ATP (3 mM) challenge for 30 min to induce optimum functioning of the inflammasome. Increased levels of NLRP3 and pro-IL-1β protein (Western) were used as readouts for inflammasome priming, while activation of caspase 1 (p20) (Western) and secretion of IL-1β (ELISA) were indicative of inflammasome activation. Results: Inhibition of PKR (PKR inhibitor or siRNA) prior to priming with LPS prevented the LPS-induced increase in NLRP3 and pro-IL-1β expression. Further, inhibition of PKR after priming, but before activation, did not affect NLRP3 or pro-IL-1β protein levels, but markedly reduced the activation of caspase 1 and secretion of mature IL-1β. In a similar fashion, a peroxynitrite decomposition catalyst (Fe-TPPS) prevented both the priming and activation of the NLRP3 inflammasome. Finally, pretreatment of the fibroblasts with Fe-TPPS prevented the LPS-induced PKR phosphorylation (T451). Conclusion: Our results indicate that peroxynitrite-/PKR pathway modulates priming and activation of NLRP3 inflammasome in LPS/ATP challenged cardiac fibroblasts.
| S-EPMC7545724 | biostudies-literature
Project description:Severe thermal injury is associated with extreme and prolonged inflammatory and hypermetabolic responses, resulting in significant catabolism that delays recovery or even leads to multiple organ failure and death. Burned patients exhibit many symptoms of stress-induced diabetes, including hyperglycemia, hyperinsulinemia, and hyperlipidemia. Recently, the nucleotide-binding domain, leucine-rich family (NLR), pyrin-containing 3 (NLRP3) inflammasome has received much attention as the sensor of endogenous "danger signals" and mediator of "sterile inflammation" in type II diabetes. Therefore, we investigated whether the NLRP3 inflammasome is activated in the adipose tissue of burned patients, as we hypothesize that, similar to the scenario observed in chronic diabetes, the cytokines produced by the inflammasome mediate insulin resistance and metabolic dysfunction.Prospective cohort study.Ross Tilley Burn Centre & Sunnybrook Research Institute.We enrolled 76 patients with burn sizes ranging from 1% to 70% total body surface area. All severely burned patients exhibited burn-induced insulin resistance and hyperglycemia.None.We examined the adipose tissue of control and burned patients and found, via flow cytometry and gene expression studies, increased infiltration of leukocytes-especially macrophages-and evidence of inflammasome priming and activation. Furthermore, we observed increased levels of interleukin-1? in the plasma of burned patients when compared to controls.In summary, our study is the first to show activation of the inflammasome in burned humans, and our results provide impetus for further investigation of the role of the inflammasome in burn-induced hypermetabolism and, potentially, developing novel therapies targeting this protein complex for the treatment of stress-induced diabetes.
| S-EPMC4166573 | biostudies-other
Project description:Nonalcoholic fatty liver disease (NAFLD), which promotes serious health problems, is related to the increase in the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome and pyroptosis by a high-fat diet (HFD). Whether dieckol (DK), a component of Ecklonia cava extracts (ECE), attenuated NAFLD in an HFD-induced NAFLD animal model was evaluated. The expression of high mobility group box 1/Toll-like receptor 4/nuclear factor-κB, which initiated the NLRP3 inflammasome, was increased in the liver of HFD-fed animals and significantly decreased with ECE or DK administration. The expression of NLRP3/ASC/caspase-1, which are components of the NLRP3 inflammasome, and the number of pyroptotic cells were increased by HFD and decreased with ECE or DK administration. The accumulation of triglycerides and free fatty acids in the liver was increased by HFD and decreased with ECE or DK administration. The histological NAFLD score was increased by HFD and decreased with ECE or DK administration. The expression of lipogenic genes (FASN, SREBP-2, PPARγ, and FABP4) increased and that of lipolytic genes (PPARα, CPT1A, ATGL, and HSL) was decreased by HFD and attenuated with ECE or DK administration. In conclusion, ECE or DK attenuated NAFLD by decreasing the NLRP3 inflammasome and pyroptosis.
| S-EPMC8227003 | biostudies-literature
Project description:Drug-induced liver injury (DILI) constitutes a clinical challenge due to the incomplete characterization of the mechanisms involved and potential risk factors. Efavirenz, an anti-HIV drug, induces deleterious actions in hepatocytes that could underlie induction of the NLRP3 inflammasome, an important regulator of inflammatory responses during liver injury. We assessed the potential of efavirenz to modulate the inflammatory and fibrogenic responses of major liver cell types involved in DILI. The effects of efavirenz were evaluated both in vitro and in vivo. Efavirenz triggered inflammation in hepatocytes, in a process that involved NF-κB and the NLRP3 inflammasome, and activated hepatic stellate cells (HSCs), thereby enhancing expression of inflammatory and fibrogenic markers. The NLRP3 inflammasome was not altered in efavirenz-treated macrophages, but these cells polarized towards the anti-inflammatory M2 phenotype and displayed upregulated anti-inflammatory mediators. Conversely, no evidence of damage was observed in efavirenz-treated animals, except when macrophages were depleted, which resulted in the in vivo manifestation of the deleterious effects detected in hepatocytes and HSCs. Efavirenz elicits a cell-specific activation of the NLRP3 inflammasome in hepatocytes and HSCs, but macrophages appear to counteract efavirenz-induced liver injury. Our results highlight the dynamic nature of the interaction among liver cell populations and emphasize the potential of targeting macrophage polarization as a strategy to treat NLRP3 inflammasome-induced liver injury.
| S-EPMC8772956 | biostudies-literature
Project description:The activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is closely associated with the development and progression of non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet. Therefore, we investigated whether oral administration of sulforaphane (SFN) prevented high-fat diet-induced NAFLD in mice by regulation of the NLRP3 inflammasome in the liver. Daily oral administrations of SFN reduced hepatic steatosis scores, serum ALT and AST levels, and hepatic levels of cholesterol, triglycerides, and free fatty acids in mice fed a high-fat diet. These were correlated with the suppression of NLRP3 inflammasome activation in the liver by SFN as evidenced by decrease in mRNA levels of ASC and caspase-1, caspase-1 enzyme activity, and IL-1β levels. SFN inhibited saturated fatty acid-induced activation of the NLRP3 inflammasome in primary mouse hepatocytes, accompanied by the restoration of mitochondrial dysfunction. The suppression of NLRP3 inflammasome by SFN was mediated by the regulation of AMP-activated protein kinase-autophagy axis. Our findings demonstrated that the suppression of NLRP3 inflammasome activation by an orally available small molecule inhibitor leads to the alleviation of the hepatic steatosis symptoms associated with NAFLD induced by a high-fat diet.
| S-EPMC4830938 | biostudies-literature