Macrophage-NLRP3 Inflammasome Activation Exacerbates Cardiac Dysfunction after Ischemic Stroke in a Mouse Model of Diabetes.
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ABSTRACT:
SUBMITTER: Lin HB
PROVIDER: S-EPMC7475163 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background/Aims: Gut microbiota has been reported to correlate with a higher mortality and worse prognosis of cardiovascular diseases. Trimethylamine N-oxide (TMAO) is a gut microbiota-dependent metabolite of specific dietary nutrients, which is linked to cardiac fibrosis. Recent reports have suggested that the activation of Nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome contributed to cardiac fibrosis. However, whether TMAO mediates cardiac fibrosis via activating NLRP3 inflammasome remains unclear. Methods and Results: To determine the role of TMAO-mediated cardiac fibrosis, we established mouse models of doxorubicin (DOX)-induced cardiac fibrosis with or without TMAO in drinking water. TMAO exacerbated DOX-induced cardiac dysfunction, heart weight and cardiac fibrosis manifested by enhanced collagen accumulation, higher profibrotic levels and elevated inflammatory factors as well as NLRP3 inflammasome activation. Using primary cultured mouse cardiac fibroblast, our results indicated that TMAO promoted proliferation, migration and collagen secretion in a dose-dependent manner by TGF-β/Smad3 signaling. Furthermore, TMAO treatment induced NLRP3 inflammasome activation including oxidative stress in cultured cardiac fibroblast. Importantly, the silencing of NLRP3 presented a protection effect against cardiac fibrosis including cellular proliferation, migration and collagen deposition in vitro. Conclusion: Our data suggested that TMAO aggravated DOX-induced mouse cardiac fibrosis, at least in part, through activation of the NLRP3 inflammasome, providing a new potential target for preventing the progression of cardiac fibrosis.
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Project description:Somatic mutations related to clonal hematopoiesis of indeterminate potential (CHIP) are risk factors for stroke. The impact of DNMT3A, the most mutated gene in CHIP, on clinical functional outcomes of acute ischemic stroke (AIS) remains unclear. In a well-characterized cohort of 8524 ischemic stroke patients, we demonstrated that DNMT3A-driven CHIP was significantly associated with neurological disability in these patients. With a stroke mouse model of transient middle cerebral artery occlusion (tMCAO), we demonstrated that DNMT3A protein levels in the brain penumbra increased. The DNMT3A inhibitor RG108 administration amplified neutrophil proliferation in the blood, promoted neutrophil infiltration into the brain penumbra, and exaggerated proinflammatory activation in tMCAO male mice. DNMT3A inhibition also significantly increased infarct volume and worsened neurobehavioral function in tMCAO male mice. In conclusion, DNMT3A somatic mutations are associated with worsened neurological disability in some patients with AIS, potentially through increased neutrophil proliferation and infiltration in the ischemic brain region. These findings suggest a possible mechanism for proinflammatory activation and tissue damage in the affected brain tissue, highlighting the need for further research in this area.
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Project description:Sterile inflammation resulting from myocardial injury activates the NLRP3 inflammasome and amplifies the inflammatory response mediating further damage.We used 2 experimental models of ischemic injury (acute myocardial infarction [AMI] with and without reperfusion) and a model of nonischemic injury due to doxorubicin 10 mg/kg to determine whether the NLRP3 inflammasome preserved cardiac function after injury.Treatment with the NLRP3 inflammasome inhibitor in the reperfused AMI model caused a significant reduction in infarct size measured at pathology or as serum cardiac troponin I level (-56% and -82%, respectively, both P < 0.001) and preserved left ventricular fractional shortening (LVFS, 31 ± 2 vs. vehicle 26% ± 1%, P = 0.003). In the non-reperfused AMI model, treatment with the NLRP3 inhibitor significantly limited LV systolic dysfunction at 7 days (LVFS of 20 ± 2 vs. 14% ± 1%, P = 0.002), without a significant effect on infarct size. In the doxorubicin model, a significant increase in myocardial interstitial fibrosis and a decline in systolic function were seen in vehicle-treated mice, whereas treatment with the NLRP3 inhibitor significantly reduced fibrosis (-80%, P = 0.001) and preserved systolic function (LVFS 35 ± 2 vs. vehicle 27% ± 2%, P = 0.017).Pharmacological inhibition of the NLRP3 inflammasome limits cell death and LV systolic dysfunction after ischemic and nonischemic injury in the mouse.
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Project description:Stroke is one of the major devastating diseases with no effective medical therapeutics. Because of the high rate of disability and mortality among stroke patients, new treatments are urgently required to decrease brain damage following a stroke. In recent years, the inflammasome is a novel breakthrough point that plays an important role in the stroke, and the inhibition of inflammasome may be an effective method for stroke treatment. Briefly, inflammasome is a multi-protein complex that causes activation of caspase-1 and subsequent production of pro-inflammatory factors including interleukin (IL)-18 and IL-1?. Among them, the NLRP3 inflammasome is the most typical inflammasome, which can detect cell damage and mediate inflammatory response to tissue damage in ischemic stroke. The NLRP3 inflammasome has become a key mediator of post-ischemic inflammation, leading to a cascade of inflammatory reactions and cell death eventually. Thus, NLRP3 inflammasome is an ideal therapeutic target due to its important role in the inflammatory response after ischemic stroke. In this mini review article, we will summarize the structure, assembly, and regulation of NLRP3 inflammasome, the role of NLRP3 inflammasome in ischemic stroke, and several treatments targeting NLRP3 inflammasome in ischemic stroke. The further understanding of the mechanism of NLRP3 inflammasome in patients with ischemic stroke will provide novel targets for the treatment of cerebral ischemic stroke patients.
| S-EPMC7283578 | biostudies-literature
Project description:Multi-protein complexes called inflammasomes have recently been identified and shown to contribute to cell death in tissue injury. Intravenous immunoglobulin (IVIg) is an FDA-approved therapeutic modality used for various inflammatory diseases. The objective of this study is to investigate dynamic responses of the NLRP1 and NLRP3 inflammasomes in stroke and to determine whether the NLRP1 and NLRP3 inflammasomes can be targeted with IVIg for therapeutic intervention. Primary cortical neurons were subjected to glucose deprivation (GD), oxygen-glucose deprivation (OGD) or simulated ischemia-reperfusion (I/R). Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion. Neurological assessment was performed, brain tissue damage was quantified, and NLRP1 and NLRP3 inflammasome protein levels were evaluated. NLRP1 and NLRP3 inflammasome components were also analyzed in postmortem brain tissue samples from stroke patients. Ischemia-like conditions increased the levels of NLRP1 and NLRP3 inflammasome proteins, and IL-1? and IL-18, in primary cortical neurons. Similarly, levels of NLRP1 and NLRP3 inflammasome proteins, IL-1? and IL-18 were elevated in ipsilateral brain tissues of cerebral I/R mice and stroke patients. Caspase-1 inhibitor treatment protected cultured cortical neurons and brain cells in vivo in experimental stroke models. IVIg treatment protected neurons in experimental stroke models by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. Our findings provide evidence that the NLRP1 and NLRP3 inflammasomes have a major role in neuronal cell death and behavioral deficits in stroke. We also identified NLRP1 and NLRP3 inflammasome inhibition as a novel mechanism by which IVIg can protect brain cells against ischemic damage, suggesting a potential clinical benefit of therapeutic interventions that target inflammasome assembly and activity.
| S-EPMC3789184 | biostudies-literature
Project description:Rationale: Stroke is a leading causes of human death worldwide. Ischemic damage induces the sterile neuroinflammation, which directly determines the recovery of patients. Lipids, a major component of the brain, significantly altered after stroke. Cholesterol sulfate, a naturally occurring analog of cholesterol, can directly regulate immune cell activation, indicating the possible involvement of cholesterol metabolites in neuroinflammation. Sulfotransferase family 2b member 1 (Sult2b1) is the key enzyme that catalyzes the synthesis of cholesterol sulfate. This study aimed to investigate the function of Sult2b1 and cholesterol sulfate in the neuroinflammation after ischemic stroke. Methods and Results: Sult2b1 -/- and wild-type mice were subjected to transient middle cerebral artery occlusion. Our data showed that Sult2b1 -/- mice had larger infarction and worse neurological scores. To determine whether immune cells were involved in the worsening stroke outcome in Sult2b1 -/- mice, bone marrow transplantation, immune cell depletion, and adoptive monocyte transfer were performed. Combined with CyTOF and immunofluorescence techniques, we demonstrated that after stroke, the peripheral monocyte-derived macrophages were the dominant cell type promoting the pro-inflammatory status in Sult2b1 -/-mice. Using primary bone marrow-derived macrophages, we showed that cholesterol sulfate could attenuate the pro-inflammatory polarization of macrophages under both normal and oxygen-glucose deprivation conditions by regulating the levels of nicotinamide adenine dinucleotide phosphate (NADPH), reactive oxygen species (ROS), and activating the AMP-activated protein kinase (AMPK) - cAMP responsive element-binding protein (CREB) signaling pathway. Conclusions: Sult2b1 -/- promoted the polarization of macrophages into pro-inflammatory status. This trend could be attenuated by adding cholesterol sulfate, which promotes the polarization of macrophages into anti-inflammatory status by metabolic regulation. In this study, we established an inflammation-metabolism axis during the macrophage polarization after ischemic stroke.
| S-EPMC8581421 | biostudies-literature
Project description:NLRP3 inflammasome-mediated pyroptosis is a proinflammatory programmed cell death pathway, which plays a vital role in functional outcomes after stroke. We previously described the beneficial effects of curcumin against stroke-induced neuronal damage through modulating microglial polarization. However, the impact of curcumin on microglial pyroptosis remains unknown. Here, stroke was modeled in mice by middle cerebral artery occlusion (MCAO) for 60 minutes and treated with curcumin (150 mg/kg) intraperitoneally immediately after reperfusion, followed by daily administrations for 7 days. Curcumin ameliorated white matter (WM) lesions and brain tissue loss 21 days poststroke and improved sensorimotor function 3, 10, and 21 days after stroke. Furthermore, curcumin significantly reduced the number of gasdermin D+ (GSDMD+) Iba1+ and caspase-1+Iba1+ microglia/macrophage 21 days after stroke. In vitro, lipopolysaccharide (LPS) with ATP treatment was used to induce pyroptosis in primary microglia. Western blot revealed a decrease in pyroptosis-related proteins, e.g., GSDMD-N, cleaved caspase-1, NLRP3, IL-1β, and IL-18, following in vitro or in vivo curcumin treatment. Mechanistically, both in vivo and in vitro studies confirmed that curcumin inhibited the activation of the NF-κB pathway. NLRP3 knocked down by siRNA transfection markedly increased the inhibitory effects of curcumin on microglial pyroptosis and proinflammatory responses, both in vitro and in vivo. Furthermore, stereotaxic microinjection of AAV-based NLRP3 shRNA significantly improved sensorimotor function and reduced WM lesion following curcumin treatment in MCAO mice. Our study suggested that curcumin reduced stroke-induced WM damage, improved functional outcomes, and attenuated microglial pyroptosis, at least partially, through suppression of the NF-κB/NLRP3 signaling pathway, further supporting curcumin as a potential therapeutic drug for stroke.
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Project description:In hyperglycemia-induced complications, macrophages play important roles in disease progression, and altered digestion is a key feature that dictates macrophage function. Recent evidence indicates that kakonein (Ka) possesses anti-inflammatory activities for hyperglycemia-induced complication. In this study, we established a mouse model of Nlrp3+/+ and Nlrp3-/- hyperglycemia and administering Ka, primary culture macrophages were tested by engulfing and digesting microbes. The role of macrophages in the cathepsin B-NLRP3 pathway involved in the mechanism of Ka in restoring macrophage digestion function was investigated using biochemical analyses, molecular biotechnology, and microbiology. Ka restored the function of macrophage digestion, which were same characterized by Nlrp3-/- mice. Meanwhile, kakonein could decrease NLRP3 inflammasome products expression and NLRP3/ASC or NLRP3/Casp1 colocalization in macrophage. Interestingly, Ka suppressed inflammasome response not by reducing NLRP3 and ASC expression but by reducing cathepsin B release and activation. And Ka restored macrophage digestion and inhibited NLRP3 inflammasome activation consistent with cathepsin B inhibitor. It is concluded that Ka reduced the release of lysosomal cathepsin B and consequently inhibited NLRP3 inflammasome activation to prevent macrophage digestion. Hence, Ka may contribute to new targets for treatment of hyperglycemia-associated dysfunction of macrophage digestion and development of innovative drugs.
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Project description:In diabetes-induced complications, inflammatory-mediated endothelial dysfunction is the core of disease progression. Evidence shows that kakonein, an isoflavone common in Pueraria, can effectively treat diabetes and its complications. Therefore, we explored whether kakonein protects cardiovascular endothelial function by inhibiting inflammatory responses. In this study, C57BL/6J mice were injected with streptozocin to establish a diabetes model and treated with kakonein or metformin for 7 days. The protective effect of kakonein on cardiovascular endothelial junctions and NLRP3 inflammasome activation was verified through immunofluorescence and ELISA assay. In addition, the regulation of autophagy on the NLRP3 inflammasome was investigated through Western blot, immunofluorescence and RT-qPCR. Results showed that kakonein restored the function of endothelial junctions and inhibited the assembly and activation of the NLRP3 inflammasome. Interestingly, kakonein decreased the expression of NLRP3 inflammasome protein by not reducing the transcriptional levels of NLRP3 and caspase-1. Kakonein activated autophagy in an AMPK-dependent manner, which reduced the activation of the NLRP3 inflammasome. In addition, kakonein inhibited both hyperglycaemia-induced cardiovascular endothelial junction dysfunction and NLRP3 inflammasome activation, similar to autophagy agonist. Our findings indicated that kakonein exerts a protective effect on hyperglycaemia-induced chronic vascular disease by regulating the NLRP3 inflammasome through autophagy.
| S-EPMC8335672 | biostudies-literature
Project description:CVD (cardiovascular disease) represents a leading cause of mortality in chronic SCI (spinal cord injury). Several component risk factors are observed in SCI; however, the underlying mechanisms that contribute to these risks have not been defined. Central and peripheral chronic inflammation is associated with metabolic dysfunction and CVD, including adipokine regulation of neuroendocrine and cardiac function and inflammatory processes initiated by the innate immune response. We use female C57 Bl/6 mice to examine neuroendocrine, cardiac, adipose and pancreatic signaling related to inflammation and metabolic dysfunction in response to experimentally induced chronic SCI. Using immuno-histochemical, -precipitation, and -blotting analysis, we show decreased POMC (proopiomelanocortin) and increased NPY (neuropeptide-Y) expression in the hypothalamic ARC (arcuate nucleus) and PVN (paraventricular nucleus), 1-month post-SCI. Long-form leptin receptor (Ob-Rb), JAK2 (Janus kinase)/STAT3 (signal transducer and activator of transcription 3)/p38 and RhoA/ROCK (Rho-associated kinase) signaling is significantly increased in the heart tissue post-SCI, and we observe the formation and activation of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome in VAT (visceral adipose tissue) and pancreas post-SCI. These data demonstrate neuroendocrine signaling peptide alterations, associated with central inflammation and metabolic dysfunction post-SCI, and provide evidence for the peripheral activation of signaling mechanisms involved in cardiac, VAT and pancreatic inflammation and metabolic dysfunction post-SCI. Further understanding of biological mechanisms contributing to SCI-related inflammatory processes and metabolic dysfunction associated with CVD pathology may help to direct therapeutic and rehabilitation countermeasures.
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