NLRP3 Is Involved in Ischemia/Reperfusion Injury

Guo, Zhiliang; Yu, Shuling; Chen, Xin; Ye, Richard D.; Zhu, Wenhui; Liu, Xinfeng

doi:10.2174/1871527315666160321111829

Cited by 83 publications

(45 citation statements)

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“…Recently, NLRP3 inflammasomes have been found in some organs after I/R injury, such as the brain, heart, kidneys, and testes [ 19 ]. As has been reported, damage-associated molecular pattern (DAMP) is the critical initial stimulus to activate NLRP3 [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction induces NLRP3 inflammasome activation during cerebral ischemia/reperfusion injury

Gong

Pan

Shen

et al. 2018

J Neuroinflammation

230

137

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BackgroundNod-like receptor protein 3 (NLRP3) inflammasome is a crucial factor in mediating inflammatory responses after cerebral ischemia/reperfusion (I/R), but the cellular location of NLRP3 inflammasome in cerebral I/R has yet come to a conclusion, and there is still no specific evidence to state the relationship between mitochondria and the NLRP3 inflammasome in cerebral I/R.MethodsIn the present study, we detected the cellular localization of NLRP3 inflammasomes in a transient middle cerebral artery occlusion (tMCAO) rat model and a transwell co-culture cell system under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions. Then, we investigated the relationship between mitochondrial dysfunction and the activation of NLRP3 inflammasomes in different cell types after OGD/R and cerebral I/R injury.ResultsOur results showed that NLRP3 inflammasomes were first activated in microglia soon after cerebral I/R injury onset and then were expressed in neurons and microvascular endothelial cells later, but they were mainly in neurons. Furthermore, mitochondrial dysfunction played an important role in activating NLRP3 inflammasomes in microglia after OGD/R, and mitochondrial protector could inhibit the activation of NLRP3 inflammasomes in cerebral I/R rats.ConclusionOur findings may provide novel insights into the cell type-dependent activation of NLRP3 inflammasomes at different stages of cerebral I/R injury and the role of mitochondrial dysfunction in activating the NLRP3 inflammasome pathway.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1282-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction induces NLRP3 inflammasome activation during cerebral ischemia/reperfusion injury

Gong

Pan

Shen

et al. 2018

J Neuroinflammation

230

137

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“…In addition, palmitate was reported to induce receptor-interacting protein (RIP)1/RIP3 activation, which mediates the form of programmed lytic cell death called “necroptosis.” RIP1/RIP3 activation also leads to the activation of Drp1, resulting in ROS production and subsequent activation of NLRP3 inflammasome ( 60 ). Evidence shows that the NLRP3 inflammasome plays a pivotal role in the ischemia/reperfusion (I/R) injury, to which diabetic subjects are more sensitive ( 61 ). Ong et al reported that the pharmacological inhibition by mdivi-1, a Drp1 inhibitor, protects the cardiac myocyte against I/R injury ( 62 ).…”

Section: Discussionmentioning

confidence: 99%

The Causal Role of Mitochondrial Dynamics in Regulating Innate Immunity in Diabetes

et al. 2020

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Background: Plenty of evidence suggested that chronic low-grade inflammation triggered by innate immunity activation contributes to the pathogenesis of type 2 diabetes (T2D). Using the trans-mitochondrial cybrid cell model, we have demonstrated that mitochondria independently take part in the pathological process of insulin resistance (IR) and pro-inflammatory phenotype in cybrid cells harboring mitochondrial haplogroup B4, which are more likely to develop T2D. The mitochondrial network is more fragmented, and the expression of fusion-related proteins is low in Cybrid B4. We also discovered the causal role of mitochondrial dynamics (mtDYN) proteins in regulating IR in this cybrid model, and the bidirectional interaction between mtDYN and mitochondrial oxidative stress is considered etiologically important. In this study, we further investigated whether mtDYN bridges the gap between nutrient excess and chronic inflammation in T2D. Methods: Trans-mitochondrial cybrid cells derived from the 143B human osteosarcoma cell line were cultured in a medium containing glucose (25 mM) with or without saturated fatty acid (0.25 mM BSA-conjugated palmitate), and the expression of innate immunity/inflammasome molecules was compared between cybrid B4 (the major T2D-susceptible haplogroup among the Chinese population) and cybrid D4 (the major T2D-resistant haplogroup among the Chinese population). We investigated the causal relationship between mtDYN and nutrient excess-induced inflammation in cybrid B4 by genetic manipulation of mtDYN and by pharmacologically inhibiting mitochondrial fission using the Drp1 inhibitor, mdivi-1, and metformin. Results: Under nutrient excess with high fatty acid, cybrid B4 presented increased mitochondrial pro-fission profiles and enhanced chronic inflammation markers (RIG-I, MDA5, MAVS) and inflammasome (NLRP3, Caspase-1, IL-1β), whereas the levels in cybrid D4 were not or less significantly altered. In cybrid B4 under nutrient excess, overexpression of fusion proteins (Mfn1 or Mfn2) significantly repressed the expression of innate immunity/inflammasome-related molecules, while knockdown had a less significant effect. On the contrary, knockdown of fission proteins (Drp1 or Fis1) significantly repressed the expression of innate immunity/inflammasome-related molecules, while overexpression had a less significant effect. In addition, Drp1 inhibitor mdivi-1 and metformin inhibited mitochondrial fission and attenuated the pro-inflammation expression as well. Conclusion: Our results discovered the causal relationship between mtDYN and nutrient excess-induced chronic inflammation in a diabetes-susceptible cell model. Targeting mtDYN by direct interfering pro-fission can be a therapeutic intervention for chronic inflammation in T2D.

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“…All three mtDNA receptors are capable of evoking cytokine and eicosanoid generation, whereas the NLRP3 initiates pyroptosis as well (43,59). The NLRP3 and TLR9 receptors have both been directly implicated in IR injury (60). Interestingly, mtDNA DAMP formation and proinflammatory ROS production may interact in a feedforward or regenerative manner.…”

Section: State Of the Artmentioning

confidence: 99%

Pharmacologic Protection of Mitochondrial DNA Integrity May Afford a New Strategy for Suppressing Lung Ischemia-Reperfusion Injury

Tan¹,

Mulekar

Gorodnya

et al. 2017

Annals ATS

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Lung ischemia-reperfusion (IR) injury contributes to post-transplant complications, including primary graft dysfunction. Decades of reports show that reactive oxygen species generated during lung IR contribute to pulmonary vascular endothelial barrier disruption and edema formation, but the specific target molecule(s) that "sense" injury-inducing oxidant stress to activate signaling pathways culminating in pathophysiologic changes have not been established. This review discusses evidence that mitochondrial DNA (mtDNA) may serve as a molecular sentinel wherein oxidative mtDNA damage functions as an upstream trigger for lung IR injury. First, the mitochondrial genome is considerably more sensitive than nuclear DNA to oxidant stress. Multiple studies suggest that oxidative mtDNA damage could be transduced to physiologic dysfunction by pathways that are either a direct consequence of mtDNA damage per se or involve formation of proinflammatory mtDNA damage-associated molecular patterns. Second, transgenic animals or cells overexpressing components of the base excision DNA repair pathway in mitochondria are resistant to oxidant stress-mediated pathophysiologic effects. Finally, published and preliminary studies show that pharmacologic enhancement of mtDNA repair or mtDNA damage-associated molecular pattern degradation suppresses reactive oxygen species-induced or IR injury in multiple organs, including preclinical models of lung procurement for transplant. Collectively, these findings point to the interesting prospect that pharmacologic enhancement of DNA repair during procurement or ex vivo lung perfusion may increase the availability of lungs for transplant and reduce the IR injury contributing to primary graft dysfunction.

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NLRP3 Is Involved in Ischemia/Reperfusion Injury

Cited by 83 publications

References 0 publications

Mitochondrial dysfunction induces NLRP3 inflammasome activation during cerebral ischemia/reperfusion injury

Mitochondrial dysfunction induces NLRP3 inflammasome activation during cerebral ischemia/reperfusion injury

The Causal Role of Mitochondrial Dynamics in Regulating Innate Immunity in Diabetes

Pharmacologic Protection of Mitochondrial DNA Integrity May Afford a New Strategy for Suppressing Lung Ischemia-Reperfusion Injury

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