Extracellular ASC exacerbated the recurrent ischemic stroke in an NLRP3-dependent manner.
Ontology highlight
ABSTRACT:
SUBMITTER: He XF
PROVIDER: S-EPMC7181081 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The NLRP3 inflammasome is an important regulator of inflammation and immunity. It is a multimolecular platform formed within cells that facilitates the activation of proinflammatory caspases to drive secretion of cytokines such as interleukin-1? (IL-1?). Knowledge of the mechanisms regulating formation of the NLRP3 inflammasome is incomplete. Here we report Cl- channel-dependent formation of dynamic ASC oligomers and inflammasome specks that remain inactive in the absence of K+ efflux. Formed after Cl- efflux exclusively, ASC specks are NLRP3 dependent, reversible, and inactive, although they further prime inflammatory responses, accelerating and enhancing release of IL-1? in response to a K+ efflux-inducing stimulus. NEK7 is a specific K+ sensor and does not associate with NLRP3 under conditions stimulating exclusively Cl- efflux, but does after K+ efflux, activating the complex driving inflammation. Our investigation delivers mechanistic understanding into inflammasome activation and the regulation of inflammatory responses.
| S-EPMC6176575 | biostudies-literature
Project description:Although the innate immune response to induce postischemic inflammation is considered as an essential step in the progression of cerebral ischemia injury, the role of innate immunity mediator NLRP3 in the pathogenesis of ischemic stroke is unknown. In this study, focal ischemia was induced by middle cerebral artery occlusion in NLRP3(-/-), NOX2(-/-), or wild-type (WT) mice. By magnetic resonance imaging (MRI), Evans blue permeability, and electron microscopic analyses, we found that NLRP3 deficiency ameliorated cerebral injury in mice after ischemic stroke by reducing infarcts and blood-brain barrier (BBB) damage. We further showed that the contribution of NLRP3 to neurovascular damage was associated with an autocrine/paracrine pattern of NLRP3-mediated interleukin-1? (IL-1?) release as evidenced by increased brain microvessel endothelial cell permeability and microglia-mediated neurotoxicity. Finally, we found that NOX2 deficiency improved outcomes after ischemic stroke by mediating NLRP3 signaling. This study for the first time shows the contribution of NLRP3 to neurovascular damage and provides direct evidence that NLRP3 as an important target molecule links NOX2-mediated oxidative stress to neurovascular damage in ischemic stroke. Pharmacological targeting of NLRP3-mediated inflammatory response at multiple levels may help design a new approach to develop therapeutic strategies for prevention of deterioration of cerebral function and for the treatment of stroke.
| S-EPMC3982086 | biostudies-other
Project description:ObjectiveTo determine black-white differences in 1-year recurrent stroke and 30-day case fatality after a recurrent stroke in older US adults.MethodsWe conducted a retrospective cohort study using a 5% random sample of Medicare beneficiaries with fee-for-service health insurance coverage who were hospitalized for ischemic stroke between 1999 and 2013. Hazard ratios for recurrent ischemic stroke and risk ratios for 30-day case fatality comparing blacks to whites were calculated with adjustment for demographics, risk factors, and competing risk of death when appropriate.ResultsAmong 128,789 Medicare beneficiaries having an ischemic stroke (mean age 80 years [SD 8 years], 60.4% male), 11.1% were black. The incidence rate of recurrent ischemic stroke per 1,000 person-years for whites and blacks was 108 (95% confidence interval [CI], 106-111) and 154 (95% CI 147-162) , respectively. The multivariable-adjusted hazard ratio for recurrent stroke among blacks compared with whites was 1.36 (95% CI 1.29-1.44). The case fatality after recurrent stroke for blacks and whites was 21% (95% CI 21%-22%) and 16% (95% CI 15%-18%), respectively. The multivariable-adjusted relative risk for mortality within 30 days of a recurrent stroke among blacks compared with whites was 0.82 (95% CI 0.73-0.93).ConclusionThe risk of stroke recurrence among older Americans hospitalized for ischemic stroke is higher for blacks compared to whites, while 30-day case fatality after recurrent stroke remains lower for blacks.
| S-EPMC6251602 | biostudies-literature
Project description:Propofol infusion syndrome (PRIS) is an uncommon life-threatening complication observed most often in patients receiving high-dose propofol. High-dose propofol treatment with a prolonged duration can damage the immune system. However, the associated molecular mechanisms remain unclear. An increasing number of clinical and experimental observations have demonstrated that tissue-resident macrophages play a critical role in immune regulation during anaesthesia and procedural sedation. Since the inflammatory response is essential for mediating propofol-induced cell death and proinflammatory reactions, we hypothesised that propofol overdose induces macrophage pyroptosis through inflammasomes. Using primary cultured bone marrow-derived macrophages, murine macrophage cell lines (RAW264.7, RAW-asc and J774) and a mouse model, we investigated the role of NLRP3 inflammasome activation and secondary pyroptosis in propofol-induced cell death. We found that high-dose propofol strongly cleaved caspase-1 but not caspase-11 and biosynthesis of downstream interleukin (IL)-1β and IL-18. Inhibition of caspase-1 activity blocks IL-1β production. Moreover, NLRP3 deletion moderately suppressed cleaved caspase-1 as well as the proportion of pyroptosis, while levels of AIM2 were increased, triggering a compensatory pathway to pyroptosis in NLRP3-/- macrophages. Here, we show that propofol-induced mitochondrial reactive oxygen species (ROS) can trigger NLRP3 inflammasome activation. Furthermore, apoptosis-associated speck-like protein (ASC) was found to mediate NLRP3 and AIM2 signalling and contribute to propofol-induced macrophage pyroptosis. In addition, our work shows that propofol-induced apoptotic initiator caspase (caspase-9) subsequently cleaved effector caspases (caspase-3 and 7), indicating that both apoptotic and pyroptotic cellular death pathways are activated after propofol exposure. Our studies suggest, for the first time, that propofol-induced pyroptosis might be restricted to macrophage through an NLRP3/ASC/caspase-1 pathway, which provides potential targets for limiting adverse reactions during propofol application. These findings demonstrate that propofol overdose can trigger cell death through caspase-1 activation and offer new insights into the use of anaesthetic drugs.
| S-EPMC6637184 | biostudies-literature
Project description:NLR family pyrin domain containing 3 (NLRP3) is a cytoplasmic pattern recognition receptor that regulates innate immune responses by forming a protein complex, the inflammasome. It leads to production of proinflammatory cytokine productions such as interleukin 1? (IL-1?). We and others demonstrated that an induction of activated NLRP3 also induced cell death. However, little is known about the characteristics and mechanisms of the cell death and its involvement in the pathogenesis of inflammatory conditions. In this study, we established cell lines in which NLRP3 was induced by doxycycline using a tetracycline-inducible expression (Tet-on) system. Using this system, the expression of NLRP3 mutants in cryopyrin-associated periodic syndrome (CAPS) patients was sufficient for the induction of necrotic cell death without lipopolysaccharide stimulation or generation of mature IL-1?. We also found that CA074-Me, a cathepsin B inhibitor, blocked cell death before oligomerization of apoptosis-associated speck-like protein containing a CARD (ASC), whereas Z-VAD-fmk, a pan-caspase inhibitor, blocked the cell death after the oligomerization. Silencing of the ASC gene (Pycard) by small hairpin RNA treatment inhibited the NLRP3 mutant-induced cell death, but silencing of the caspase-1 gene (Casp1) did not. Taken together, these results indicated that ASC was indispensable for NLRP3-mediated programmed necrotic cell death, and that this type of cell death was distinct from 'pyroptosis', which requires caspase-1. Finally, we demonstrated in an in vivo model that the programmed necrotic cell death induced by activated NLRP3 could cause neutrophil infiltration, indicating a possible role of cell death in neutrophil infiltration of skin lesions in CAPS patients.
| S-EPMC3674376 | biostudies-literature
Project description:The inflammasome adaptor protein, ASC, contributes to both innate immune responses and inflammatory diseases via self-oligomerization, which leads to the activation of the protease, caspase-1. Here, we report that the cytosolic tyrosine kinases, FAK and Pyk2, are differentially involved in NLRP3 and AIM2 inflammasome activation. The inhibition of FAK and Pyk2 with RNA interference or chemical inhibitors dramatically abolished ASC oligomerization, caspase-1 activation, and IL-1? secretion in response to NLRP3 or AIM2 stimulation. Pyk2 is phosphorylated by the kinase Syk and relocalizes to the ASC specks upon NLRP3 inflammasome activation. Pyk2, but not FAK, could directly phosphorylate ASC at Tyr146, and only the phosphorylated ASC could participate in speck formation and trigger IL-1? secretion. Moreover, the clinical-trial-tested Pyk2/FAK dual inhibitor PF-562271 reduced monosodium urate-mediated peritonitis, a disease model used for studying the consequences of NLRP3 activation. Our results suggest that although Pyk2 and FAK are involved in inflammasome activation, only Pyk2 directly phosphorylates ASC and brings ASC into an oligomerization-competent state by allowing Tyr146 phosphorylation to participate ASC speck formation and subsequent NLRP3 inflammation.
| S-EPMC5087076 | biostudies-literature
Project description:IntroductionThe protein platform called the NOD-like-receptor -family member (NLRP)-3 inflammasome needs to be activated to process intracellular caspase-1. Active caspase-1 is able to cleave pro-Interleukin (IL)-1?, resulting in bioactive IL-1?. IL-1? is a potent proinflammatory cytokine, and thought to play a key role in the pathogenesis of Lyme arthritis, a common manifestation of Borrelia burgdorferi infection. The precise pathways through which B. burgdorferi recognition leads to inflammasome activation and processing of IL-1? in Lyme arthritis has not been elucidated. In the present study, we investigated the contribution of several pattern recognition receptors and inflammasome components in a novel murine model of Lyme arthritis.MethodsLyme arthritis was elicited by live B. burgdorferi, injected intra-articularly in knee joints of mice. To identify the relevant pathway components, the model was applied to wild-type, NLRP3-/-, ASC-/-, caspase-1-/-, NOD1-/-, NOD2-/-, and RICK-/- mice. As a control, TLR2-/-, Myd88-/- and IL-1R-/- mice were used. Peritoneal macrophages and bone marrow-derived macrophages were used for in vitro cytokine production and inflammasome activation studies. Joint inflammation was analyzed in synovial specimens and whole knee joints. Mann-Whitney U tests were used to detect statistical differences.ResultsWe demonstrate that ASC/caspase-1-driven IL-1? is crucial for induction of B. burgdorferi-induced murine Lyme arthritis. In addition, we show that B. burgdorferi-induced murine Lyme arthritis is less dependent on NOD1/NOD2/RICK pathways while the TLR2-MyD88 pathway is crucial.ConclusionsMurine Lyme arthritis is strongly dependent on IL-1 production, and B. burgdorferi induces inflammasome-mediated caspase-1 activation. Next to that, murine Lyme arthritis is ASC- and caspase-1-dependent, but NLRP3, NOD1, NOD2, and RICK independent. Also, caspase-1 activation by B. burgdorferi is dependent on TLR2 and MyD88. Based on present results indicating that IL-1 is one of the major mediators in Lyme arthritis, there is a rationale to propose that neutralizing IL-1 activity may also have beneficial effects in chronic Lyme arthritis.
| S-EPMC3674595 | biostudies-literature
Project description:(1) Background: Patients with benign prostatic hyperplasia (BPH) were questioned about quality of life and sleep. Most BPH patients were treated with alpha-1 adrenergic receptor antagonists, which could improve cerebral blood flow for 1-2 months. Patients with ischemic stroke (IS) could experience cerebral autoregulation impairment for six months. The relationship between BPH and recurrent IS remains unclear. The aim of this study was to determine the risk of one-year recurrent IS conferred by BPH. (2) Methods: We used data from the Taiwanese National Health Insurance Database to identify newly diagnosed IS cases entered from 1 January 2008 to 31 December 2008. Patients were followed until the recurrent IS event or 365 days after the first hospitalization. The risk factors associated with one-year recurrent IS were assessed using Cox proportional hazards regression. (3) Results: Patients with BPH had a higher risk of recurrent IS (12.11% versus 8.15%) (adjusted hazard ratio (HR): 1.352; 95% confidence interval (CI): 1.028-1.78, p = 0.031). Other risk factors included hyperlipidemia (adjusted HR: 1.338; 95% CI: 1.022-1.751, p = 0.034), coronary artery disease (adjusted HR: 1.487; 95% CI: 1.128-1.961, p = 0.005), chronic obstructive pulmonary disease (adjusted HR: 1.499; 95% CI: 1.075-2.091, p = 0.017), and chronic kidney disease (adjusted HR: 1.523; 95% CI: 1.033-2.244, p = 0.033). (4) Conclusion: Patients with BPH who had these risk factors had an increased risk of one-year recurrent IS. The modification of risk factors may prevent recurrent IS.
| S-EPMC7432020 | biostudies-literature
Project description:BACKGROUND:We aimed to determine the risk conferred by metabolic syndrome (METS) and diabetes mellitus (DM) to recurrent stroke in patients with minor ischemic stroke or transient ischemic attack from the CHANCE (Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events) trial. METHODS AND RESULTS:In total, 3044 patients were included. Patients were stratified into 4 groups: neither, METS only, DM only, or both. METS was defined using the Chinese Diabetes Society (CDS) and International Diabetes Foundation (IDF) definitions. The primary outcome was new stroke (including ischemic and hemorrhagic) at 90 days. A multivariable Cox regression model was used to assess the relationship of METS and DM status to the risk of recurrent stroke adjusted for potential covariates. Using the CDS criteria of METS, 53.2%, 17.2%, 19.8%, and 9.8% of patients were diagnosed as neither, METS only, DM only, and both, respectively. After 90 days of follow-up, there were 299 new strokes (293 ischemic, 6 hemorrhagic). Patients with DM only (16.1% versus 6.8%; adjusted hazard ratio 2.50, 95% CI 1.89-3.39) and both (17.1% versus 6.8%; adjusted hazard ratio 2.76, 95% CI 1.98-3.86) had significantly increased rates of recurrent stroke. No interaction effect of antiplatelet therapy by different METS or DM status for the risk of recurrent stroke (P=0.82 for interaction in the fully adjusted model of CDS) was observed. Using the METS (IDF) criteria demonstrated similar results. CONCLUSIONS:Concurrent METS and DM was associated with an increased risk of recurrent stroke in patients with minor stroke and transient ischemic attack.
| S-EPMC5669168 | biostudies-literature
Project description:Background Many patients after stroke are found to have elevated serum creatine kinase (CK). This study aimed to investigate the associations between serum CK levels and clinical outcomes in patients with acute ischemic stroke or transient ischemic attack. Methods and Results The study included 8910 patients with acute ischemic stroke or transient ischemic attack from the CNSR-III (Third China National Stroke Registry). Baseline serum CK levels after admission were measured. The associations between CK and clinical outcomes (stroke recurrence, death, and disability, defined as modified Rankin scale score 3-6 or 2-6) were analyzed. Patients with elevated CK levels had higher risks of recurrent stroke (hazard ratio [HR], 1.53; 95% CI, 1.21-1.93), death (HR, 1.68; 95% CI, 1.10-2.58), and disability (modified Rankin scale score, 3-6; odds ratio, 1.57; 95% CI, 1.29-1.90) at 3 months after adjusting confounding factors. Similar results were found at 1 year. The effects of CK on death and disability were more significant in male patients than female patients (P value for interaction <0.05). Elevated CK-MB levels were not associated with clinical outcomes in this study. Conclusions Elevated serum CK after ischemic stroke or transient ischemic attack is associated with higher risks of recurrent stroke, death, and disability at 3 months and 1 year. Serum CK may act as a useful predictor for recurrent stroke and poor functional outcomes in patients with acute ischemic stroke or transient ischemic attack. Sex modifies the relationship between elevated CK and disability or death.
| S-EPMC9075278 | biostudies-literature