Hypoxia Inducible Factor-1α (HIF-1α) Mediates NLRP3 Inflammasome-Dependent-Pyroptotic and Apoptotic Cell Death Following Ischemic Stroke

Jiang, Qian; Xu, Geng; Warren, John W.; Cosky, Eric E; Kaura, Shawn; Stone, Christopher; Li, Fengwu; Ding, Yuchuan

doi:10.1016/j.neuroscience.2020.09.036

Cited by 123 publications

(89 citation statements)

References 45 publications

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“…It is possible that HIF-1α regulates the metabolic modes of cells, which can adapt to shortterm hypoxia, but cannot adapt to long-term hypoxia. The final outcome of HIF-1α depends on the balance between various factors and reactions (41,42).…”

Section: Discussionmentioning

confidence: 99%

The protective effects of exogenous spermine on renal ischemia-reperfusion injury in rats

Yan¹,

Min²,

Xu³

et al. 2021

Transl Androl Urol

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Background: To investigate the protective effects of exogenous spermine on renal ischemia-reperfusion injury in rats.Methods: (I) Different doses of spermine were injected into rats to determine the safe dose on the kidneys. Kidney toxicity was assessed by hematoxylin and eosin (HE) staining of kidney tissue and enzyme-linked immunosorbent assay (ELISA) detection of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) in the venous blood. (II) A rat model of renal ischemia-reperfusion injury was established. Different doses of spermine were injected into the rats through the tail vein 30 minutes before and 3 days after the establishment of the model. Blood samples and kidney tissues were collected and renal injury was assessed via HE staining of the renal tissue, detection of apoptosis using the TUNEL assay, and detection of NGAL and KIM-1 in blood samples using ELISA. (III) Human HK-2 renal tubular epithelial cells were cultured under hypoxia/reoxygenation conditions. To evaluate the protective effects of spermine, apoptosis was assessed by flow cytometry and TUNEL assay. The mechanisms underlying the effects of spermine were studied using Western blot analyses.Results: At spermine concentrations below 200 μM (2 mL/kg body weight), no significant damage to the kidney was observed by HE staining, and there was no significant difference in NGAL and KIM-1 levels between rats treated with spermine and control rats (P<0.05). At spermine doses below 200 μM, HE staining showed that the degree of renal ischemia-reperfusion injury was gradually alleviated with increasing doses of spermine. TUNEL assays demonstrated that spermine reduced the apoptosis of renal tissue, and increasing doses of spermine gradually decreased the levels of NGAL and KIM-1 in the blood compared with the control group (P<0.05). Western blot analysis revealed that spermine increased the expression of pro-caspase9, phosphorylated protein kinase B (p-Akt), hypoxia-inducible factor 1 alpha (HIF-1α), B cell lymphoma 2 (Bcl-2), and Bcl2 interacting protein 3 (BNIP3), and decreased the expression of cleaved caspase-3, Bax and cytochrome C compared to control cells.Conclusions: Exogenous spermine exerted a protective effect on renal ischemia-reperfusion injury in rats by inhibiting the apoptosis of renal tubular epithelial cells.

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Section: Discussionmentioning

confidence: 99%

The protective effects of exogenous spermine on renal ischemia-reperfusion injury in rats

Yan¹,

Min²,

Xu³

et al. 2021

Transl Androl Urol

View full text Add to dashboard Cite

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“…It is however unknown whether it relies on an LXR-dependent mechanism (161) ( Table 1). However, as HIF1a induces NLRP3 inflammasome activation (179)(180)(181), such regulatory mechanism may then account for LXR-dependent activation of IL1-b production in hypoxic atherosclerotic lesions. Diabetes and hypertension are common coexisting diseases that accelerate micro and macrovascular complication occurrence.…”

Section: Cardiometabolic Diseasesmentioning

confidence: 99%

“…It is however unknown whether it relies on an LXR-dependent mechanism ( 161 ) ( Table 1 ). However, as HIF1 α induces NLRP3 inflammasome activation ( 179 – 181 ), such regulatory mechanism may then account for LXR-dependent activation of IL1-β production in hypoxic atherosclerotic lesions.…”

Section: Regulatory Function Of Nr In Nlrp3-driven Diseases and Theirmentioning

confidence: 99%

Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway

Duez

Pourcet

2021

Front. Endocrinol.

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The innate immune system is the first line of defense specialized in the clearing of invaders whether foreign elements like microbes or self-elements that accumulate abnormally including cellular debris. Inflammasomes are master regulators of the innate immune system, especially in macrophages, and are key sensors involved in maintaining cellular health in response to cytolytic pathogens or stress signals. Inflammasomes are cytoplasmic complexes typically composed of a sensor molecule such as NOD-Like Receptors (NLRs), an adaptor protein including ASC and an effector protein such as caspase 1. Upon stimulation, inflammasome complex components associate to promote the cleavage of the pro-caspase 1 into active caspase-1 and the subsequent activation of pro-inflammatory cytokines including IL-18 and IL-1β. Deficiency or overactivation of such important sensors leads to critical diseases including Alzheimer diseases, chronic inflammatory diseases, cancers, acute liver diseases, and cardiometabolic diseases. Inflammasomes are tightly controlled by a two-step activation regulatory process consisting in a priming step, which activates the transcription of inflammasome components, and an activation step which leads to the inflammasome complex formation and the subsequent cleavage of pro-IL1 cytokines. Apart from the NF-κB pathway, nuclear receptors have recently been proposed as additional regulators of this pathway. This review will discuss the role of nuclear receptors in the control of the NLRP3 inflammasome and the putative beneficial effect of new modulators of inflammasomes in the treatment of inflammatory diseases including colitis, fulminant hepatitis, cardiac ischemia–reperfusion and brain diseases.

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“…In retinal pigmented epithelial cells, hypoxia induced expression of NLRP3 and IL-1β in a pathway dependent upon ATP release and the P2Y12 receptor, and inflammasome activation killed cells only under hypoxic conditions ( Doktor et al, 2018 ). HIF-1α is implicated in hypoxia-mediated inflammasome priming as blockage of HIF-1α reduced expression of NLRP3, caspase 1 and IL-1β and of pyroptotic death in a stroke model ( Jiang et al, 2020 ).…”

Section: Hypoxia Contributes To Inflammationmentioning

confidence: 99%

Crosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration

2021

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Mitochondrial dysfunction and excessive inflammatory responses are both sufficient to induce pathology in age-dependent neurodegenerations. However, emerging evidence indicates crosstalk between damaged mitochondrial and inflammatory signaling can exacerbate issues in chronic neurodegenerations. This review discusses evidence for the interaction between mitochondrial damage and inflammation, with a focus on glaucomatous neurodegeneration, and proposes that positive feedback resulting from this crosstalk drives pathology. Mitochondrial dysfunction exacerbates inflammatory signaling in multiple ways. Damaged mitochondrial DNA is a damage-associated molecular pattern, which activates the NLRP3 inflammasome; priming and activation of the NLRP3 inflammasome, and the resulting liberation of IL-1β and IL-18 via the gasdermin D pore, is a major pathway to enhance inflammatory responses. The rise in reactive oxygen species induced by mitochondrial damage also activates inflammatory pathways, while blockage of Complex enzymes is sufficient to increase inflammatory signaling. Impaired mitophagy contributes to inflammation as the inability to turnover mitochondria in a timely manner increases levels of ROS and damaged mtDNA, with the latter likely to stimulate the cGAS-STING pathway to increase interferon signaling. Mitochondrial associated ER membrane contacts and the mitochondria-associated adaptor molecule MAVS can activate NLRP3 inflammasome signaling. In addition to dysfunctional mitochondria increasing inflammation, the corollary also occurs, with inflammation reducing mitochondrial function and ATP production; the resulting downward spiral accelerates degeneration. Evidence from several preclinical models including the DBA/2J mouse, microbead injection and transient elevation of IOP, in addition to patient data, implicates both mitochondrial damage and inflammation in glaucomatous neurodegeneration. The pressure-dependent hypoxia and the resulting metabolic vulnerability is associated with mitochondrial damage and IL-1β release. Links between mitochondrial dysfunction and inflammation can occur in retinal ganglion cells, microglia cells and astrocytes. In summary, crosstalk between damaged mitochondria and increased inflammatory signaling enhances pathology in glaucomatous neurodegeneration, with implications for other complex age-dependent neurodegenerations like Alzheimer’s and Parkinson’s disease.

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Hypoxia Inducible Factor-1α (HIF-1α) Mediates NLRP3 Inflammasome-Dependent-Pyroptotic and Apoptotic Cell Death Following Ischemic Stroke

Cited by 123 publications

References 45 publications

The protective effects of exogenous spermine on renal ischemia-reperfusion injury in rats

The protective effects of exogenous spermine on renal ischemia-reperfusion injury in rats

Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway

Crosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration

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