Aprepitant attenuates NLRC4-dependent neuronal pyroptosis via NK1R/PKCδ pathway in a mouse model of intracerebral hemorrhage

Jin, Peng; Qi, Dongqing; Y, Cui; Lenahan, Cameron; Zhang, Junyi; Tao, Xiaogen; Deng, Shuixiang; Tang, Jiping

doi:10.1186/s12974-022-02558-z

Cited by 15 publications

(9 citation statements)

References 59 publications

(81 reference statements)

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“… 13 In contrast, knocking down NLRC4 using siRNA exerted neuroprotective effects in experimental intracerebral hemorrhage. 20 In addition, similar results were found in ischemic stroke using siRNA knockdown of NLRC4. 14 In the current study, serum NLRC4 levels were independently correlated with serum C-reactive protein levels.…”

Section: Discussionsupporting

confidence: 67%

“…NLRC4 is a very important component of inflammasome. 19 NLRC4 was highly expressed in brain tissues of mice after intracerebral hemorrhage in a time-dependent manner, with peaking at post-hemorrhage 24 h. 20 In addition, the highest expression of rat NLRC4 in ischemia area was revealed at 4h of transient cerebral ischemia/reperfusion. 21 Moreover, NLRC4 was dominantly located in neurons after animal cerebral ischemia 22 and in glial cells under lysophosphatidylcholine, a molecule associated with neurodegeneration and demyelination.…”

Section: Discussionmentioning

confidence: 96%

See 1 more Smart Citation

Evaluation of Serum NLRC4 as a Potential Prognostic Biochemical Marker in Humans with Severe Traumatic Brain Injury: A Prospective Cohort Study

Tang¹,

Zhong²,

Wu³

et al. 2023

RMHP

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Objective Involvement of NLR CARD domain containing 4 (NLRC4) in neuroinflammation has been demonstrated. The aim of this study was to ascertain the prognostic role of serum NLRC4 in severe traumatic brain injury (sTBI). Methods In this prospective cohort study including 140 sTBI patients and 140 controls, serum NLRC4 levels were quantified. Follow-up time was 180 days after trauma and poor prognosis was designated as extended Glasgow outcome scale (GOSE) scores of 1–4. Severity correlations and prognosis associations were determined under multivariate models. Results Enhanced serum NLRC4 levels after sTBI, in comparison to controls (median, 0.8 ng/mL versus 0.1 ng/mL; P < 0.001), were independently correlated with Glasgow coma scale (GCS) scores (β, −0.091; 95% confidence interval (CI), −0.161—0.021; P = 0.011), Rotterdam computed tomography (CT) scores (β, 0.136; 95% CI, 0.024–0.248; P = 0.018), serum C-reactive protein levels (β, 0.016; 95% CI, 0.002–0.030; P = 0.025) and 180-day GOSE scores (β, −0.906; 95% CI, −1.632—0.180; P = 0.015); and were independently predictive of 180-day death (odds ratio, 4.307; 95% CI, 1.706–10.879; P = 0.014)), overall survival (hazard ratio, 2.360; 95% CI, 1.118–4.981; P = 0.040) and poor prognosis (odds ratio, 6.705; 95% CI, 2.889–15.561; P = 0.016). Under receiver operating characteristic curve, combination of serum NLRC4 levels, GCS scores and Rotterdam CT scores had significantly higher death predictive ability than Rotterdam CT scores (P = 0.040), but not than GCS scores (P = 0.070); and exhibited substantially higher predictive capability for poor prognosis than Rotterdam CT scores (P < 0.001) and GCS scores alone (P = 0.023). Conclusion There is a dramatical elevation of serum NLRC4 levels after sTBI, which has strong correlation with severity and inflammation, and is significantly associated with long-term death and poor outcome, substantializing serum NLRC4 as an inflammatory, prognostic biomarker in sTBI.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 96%

Evaluation of Serum NLRC4 as a Potential Prognostic Biochemical Marker in Humans with Severe Traumatic Brain Injury: A Prospective Cohort Study

Tang¹,

Zhong²,

Wu³

et al. 2023

RMHP

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“…NLRC4 is a member of them and is responsible to process prointerleukin-1beta and pro-interleukin-18 into a maturation state to promote inflammation (19). A previous experimental study showed that NLRC4 expressions were enhanced in a timedependent manner following ICH, and peaked at 24 h following ICH (20). Another animal study demonstrated that there was a substantial upregulation of NLRC4 expressions after cerebral ischemia and NLRC4 was mainly localized in neurons (21).…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of serum NLRC4 in patients with acute supratentorial intracerebral hemorrhage: A prospective longitudinal cohort study

Li²,

Ma³

et al. 2023

Front. Neurol.

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ObjectiveCaspase activation and recruitment domain-containing protein 4 (NLRC4) is implicated in neuroinflammation. The aim of the study was to discern the potential ability of serum NLRC4 in assessment of prognosis after intracerebral hemorrhage (ICH).MethodsIn this prospective, observational study, serum NLRC4 levels were quantified in 148 acute supratentorial ICH patients and 148 controls. Severity was evaluated using the National Institutes of Health Stroke Scale (NIHSS) and hematoma volume, and poststroke 6-month functional outcome was estimated according to the modified Rankin Scale (mRS). Early neurologic deterioration (END) and 6-month poor outcome (mRS 3–6) were deemed as the two prognostic parameters. Multivariate models were established for investigating associations, and receiver operating characteristic (ROC) curves were configured to indicate predictive capability.ResultsPatients had substantially higher serum NLRC4 levels than controls (median, 363.2 pg/ml vs. 74.7 pg/ml). Serum NLRC4 levels had independent correlation with NIHSS scores [β, 0.308; 95% confidence interval (CI), 0.088–0.520], hematoma volume (β, 0.527; 95% CI, 0.385–0.675), serum C-reactive protein levels (β, 0.288; 95% CI, 0.109–0.341) and 6-month mRS scores (β, 0.239; 95% CI, 0.100–0.474). Serum NLRC4 levels above 363.2 pg/ml were independently predictive of END (odds ratio, 3.148; 95% CI, 1.278–7.752) and 6-month poor outcome (odds ratio, 2.468; 95% CI, 1.036–5.878). Serum NLRC4 levels significantly distinguished END risk [area under ROC curve (AUC), 0.765; 95% CI, 0.685–0.846] and 6-month poor outcome (AUC, 0.795; 95% CI, 0.721–0.870). In terms of predictive ability for 6-month poor outcome, serum NLRC4 levels combined with NIHSS scores and hematoma volume was superior to NIHSS scores combined with hematoma volume, NIHSS scores and hematoma volume (AUC, 0.913 vs. 0.870, 0.864 and 0.835; all P < 0.05). Nomograms were built to reflect prognosis and END risk of combination models, where serum NLRC4, NIHSS scores and hematoma volume were enforced. Calibration curves confirmed stability of combination models.ConclusionsMarkedly raised serum NLRC4 levels following ICH, in close relation to illness severity, are independently associated with poor prognosis. Such results are indicative of the notion that determination of serum NLRC4 may aid in severity assessment and prediction of functional outcome of ICH patients.

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“…Intracerebral hemorrhage (ICH), defined as a brain injury caused by acute bleeding into the brain parenchyma from a ruptured cerebral blood vessel [1], is arguably the most lethal form of acute stroke [2]. The early-term mortality of ICH is around 40%, with no significant improvement over the past three decades [3,4].…”

Section: Introductionmentioning

confidence: 99%

“…Nlrc4 could be upregulated after arterial blood was drawn from rats and injected into the basal ganglia (to simulate the ICH model), and the elimination of Nlrc4 was demonstrated to attenuate neuronal death, cerebral swelling and neurological deficits following ICH [8]. Additionally, the inhibition of Nlrc4-dependent pyroptosis was proved to be beneficial for neurological function [2]. However, the mechanism of Nlrc4-dependent neuronal pyroptosis in ICH remains unclear and requires further investigation.…”

Section: Introductionmentioning

confidence: 99%

Egr1 promotes Nlrc4-dependent neuronal pyroptosis through phlda1 in an in-vitro model of intracerebral hemorrhage

Wang,

Gu,

Jin

et al. 2024

NeuroReport

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Intracerebral hemorrhage (ICH) is a fatal brain injury, but the current treatments for it are inadequate to reduce the severity of secondary brain injury. Our study aims to explore the molecular mechanism of Egr1 and Phlda1 in regulating hemin-induced neuronal pyroptosis, and hope to provide novel therapeutic targets for ICH treatment. Mouse hippocampal neuron cells treated with hemin were used to simulate an in-vitro ICH model. Using qRT-PCR and western blot to evaluate mRNA and protein concentrations. MTT assay was utilized to assess cell viability. LDH levels were determined by lactate Dehydrogenase Activity Assay Kit. IL-1β and IL-18 levels were examined by ELISA. The interaction of Egr1 and Phlda1 promoter was evaluated using chromatin immunoprecipitation and dual-luciferase reporter assays. Egr1 and Phlda1 were both upregulated in HT22 cells following hemin treatment. Hemin treatment caused a significant reduction in HT22 cell viability, an increase in Nlrc4 and HT22 cell pyroptosis, and heightened inflammation. However, knocking down Egr1 neutralized hemin-induced effects on HT22 cells. Egr1 bound to the promoter of Phlda1 and transcriptionally activated Phlda1. Silencing Phlda1 significantly reduced Nlrc4-dependent neuronal pyroptosis. Conversely, overexpressing Phlda1 mitigated the inhibitory effects of Egr1 knockdown on Nlrc4 and neuronal pyroptosis during ICH. Egr1 enhanced neuronal pyroptosis mediated by Nlrc4 under ICH via transcriptionally activating Phlda1.

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Aprepitant attenuates NLRC4-dependent neuronal pyroptosis via NK1R/PKCδ pathway in a mouse model of intracerebral hemorrhage

Cited by 15 publications

References 59 publications

Evaluation of Serum NLRC4 as a Potential Prognostic Biochemical Marker in Humans with Severe Traumatic Brain Injury: A Prospective Cohort Study

Evaluation of Serum NLRC4 as a Potential Prognostic Biochemical Marker in Humans with Severe Traumatic Brain Injury: A Prospective Cohort Study

Prognostic significance of serum NLRC4 in patients with acute supratentorial intracerebral hemorrhage: A prospective longitudinal cohort study

Egr1 promotes Nlrc4-dependent neuronal pyroptosis through phlda1 in an in-vitro model of intracerebral hemorrhage

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