Hypercapnia promotes microglial pyroptosis via inhibiting mitophagy in hypoxemic adult rats

Ding, Hongguang; Li, Ya; Li, Xu‐sheng; Liu, Xin‐qiang; Wang, Kang‐rong; Wen, Miaowen; Zeng, Hongke

doi:10.1111/cns.13435

Cited by 24 publications

(15 citation statements)

References 45 publications

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“…Recently, activation of mitophagy has been demonstrated to be a vital protective mechanism of MSC-exos against different diseases [ 24 , 25 ]. Importantly, the inhibitory effect of mitophagy on pyroptosis has been demonstrated in several reports [ 23 , 29 , 30 ]. In accordance with these results, the present study showed that MSC-exos treatment significantly upregulated the levels of mitophagy-related proteins in OGD/R-exposed BV-2 cells.…”

Section: Discussionmentioning

confidence: 94%

“…Previous studies demonstrated that inhibition of mitophagy contributes to microglial pyroptosis [ 23 , 29 , 30 ]. Thus, we wondered whether mitophagy is involved in the protective effect of MSC-exos against OGD/R-induced microglial pyroptosis.…”

Section: Resultsmentioning

confidence: 99%

“…Mitophagy, a way to clear damaged mitochondria, plays a vital role in the activation and survival of microglia [ 20 – 22 ]. A recent study has showed that hypercapnia promotes microglial pyroptosis by inhibiting mitophagy in hypoxemic adult rats [ 23 ], suggesting that mitophagy acts as a negative regulator of microglial pyroptosis. To date, the effect of mitophagy on I/R-induced microglial pyroptosis remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Human Umbilical Cord Mesenchymal Stem Cell‐Derived Exosomes Attenuate Oxygen‐Glucose Deprivation/Reperfusion‐Induced Microglial Pyroptosis by Promoting FOXO3a‐Dependent Mitophagy

Yuan

Zhang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Background. Mesenchymal stem cell-derived exosomes (MSC-exos) have been recognized as a promising therapeutic strategy for neonatal hypoxic-ischemic brain damage (HIBD). Recently, microglial pyroptosis was shown to play a vital role in the progression of neonatal HIBD. However, whether MSC-exos improve HIBD by regulating microglial pyroptosis remains unknown. Methods. Exosomes were isolated from human umbilical cord mesenchymal stem cells (huMSCs) and identified by transmission electron microscopy (TEM), western blot, and nanoparticle tracking analysis (NTA). BV-2 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to induce microglial ischemia/reperfusion (I/R) in vitro. CCK-8, ELISA, western blot, and Hoechst 33342/PI double staining were performed to detect the pyroptosis of BV-2 cells. Conditioned medium (CM) from BV-2 cells exposed to different treatments was used to investigate its effect on neuronal injury. Moreover, 3-methyladenine (3-MA) and mitochondrial division inhibitor-1 (mdi-1) were used to verify the involvement of mitophagy in the protection of MSC-exos against OGD/R-induced pyroptosis in BV-2 cells. Finally, FOXO3a siRNA was used to investigate the involvement of FOXO3a in MSC-exo-induced mitophagy and pyroptosis inhibition. Results. Exosomes from huMSCs were successfully extracted. In OGD/R-exposed BV-2 cells, MSC-exos increased cell viability and decreased the expression of NLRP3, cleaved caspase-1, and GSDMD-N as well as the release of IL-1β and IL-18. Compared with CM from OGD/R-exposed BV-2 cells treated with PBS, CM from OGD/R-exposed BV-2 cells treated with MSC-exos significantly increased the viability of SH-SY5Y cells and decreased LDH release. MSC-exos also increased the expression of TOM20 and COX IV in OGD/R-exposed BV-2 cells. Additionally, 3-MA and mdi-1 attenuated the inhibition of pyroptosis with MSC-exo treatment. Furthermore, FOXO3a siRNA partially abolished the neuroprotective effect of MSC-exos and attenuated mitophagy and pyroptosis inhibition induced by MSC-exo treatment. Conclusions. Our findings demonstrated that MSC-exos increased FOXO3a expression to enhance mitophagy, therefore protecting microglia from I/R-induced pyroptosis and alleviating subsequent neuronal injury.

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Section: Discussionmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human Umbilical Cord Mesenchymal Stem Cell‐Derived Exosomes Attenuate Oxygen‐Glucose Deprivation/Reperfusion‐Induced Microglial Pyroptosis by Promoting FOXO3a‐Dependent Mitophagy

Yuan

Zhang

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…DG21175D) was used to detect the level of ROS. 15 Based on the manufacturer's instruction, the brain tissue samples were homogenized and then added into the special plate coated with antibodies that could capture ROS. After one‐hour incubation at 37°C, substrate A and B were added successively.…”

Section: Methodsmentioning

confidence: 99%

Fisetin ameliorates cognitive impairment by activating mitophagy and suppressing neuroinflammation in rats with sepsis‐associated encephalopathy

Ding

Chen

et al. 2021

CNS Neurosci Ther

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Background Fisetin, the effective ingredient of the traditional Chinese medicine named Cotinus coggygria, is recommended to be active therapeutic in many disorders. However, its role in sepsis‐associated encephalopathy (SAE) remains unclarified. Methods Cecal ligation and puncture (CLP) operation was performed to establish a rat model of SAE. Rats were grouped according to the surgery operation and fisetin administration. Cognitive impairment was assessed by Morris water maze test. Disruption of blood‐brain barrier (BBB) integrity was detected by Evan's blue staining. The mitophagy, reactive oxygen species (ROS) generation, NLRP3 inflammasome activation, and pro‐inflammatory cytokines levels were measured through western blot and double immunofluorescence labeling. A transmission electron microscope was applied for the observation of mitochondrial autophagosomes. Results Rats in the CLP group presented increased expression of IL‐1R1, pNF‐κB, TNF‐α, and iNOS in microglial cells, indicating severe inflammation in the central nervous system (CNS). Nevertheless, there was no increase in BBB permeability. Meanwhile, NLRP3 inflammasome was activated in cerebral microvascular endothelial cells (CMECs), presented with an elevation of caspase‐1 expression and IL‐1β secretion into CNS. In addition, we found fisetin significantly improved cognitive dysfunction in rats with SAE. Neuroprotective effects of fisetin might be associated with inhibition of neuroinflammation, represented with decreased expression of IL‐1R1, pNF‐κB, TNF‐α, and iNOS in microglia. Furthermore, fisetin induced mitophagy, scavenged ROS, blocked NLRP3 inflammasome activation of CMECs, as evidenced by decreased expression of caspase‐1 and reduced release of IL‐1β into CNS. Conclusion Collectively, fisetin‐blocked NLRP3 inflammasome activation via promoting mitophagy in CMECs may suppress the secretion of IL‐1β into CNS, reduce neuroinflammation, and contribute to the amelioration of cognitive impairment.

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“…Additionally, many studies in recent years have shown a complex link between mitophagy and pyroptosis. The current prevailing view is that there is a negative feedback regulation between mitophagy and pyroptosis (Yu et al, 2019 ; Davidson et al, 2020 ; Ding et al, 2020 ). Activation of caspase-1 caused by inflammasome would inhibit mitophagy and further enhance mitochondrial damage.…”

Section: Interactions Between Pyroptosis and Mitochondrial Apoptosismentioning

confidence: 99%

The Role of Mitochondria in Pyroptosis

Shi

Cai

et al. 2021

Front. Cell Dev. Biol.

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Pyroptosis is a recently discovered aspartic aspart-specific cysteine protease (Caspase-1/4/5/11) dependent mode of gene-regulated cell death cell death, which is represented by the rupture of cell membrane perforations and the production of proinflammatory mediaters like interleukin-18(IL-18) and interleukin-1β (IL-1β). Mitochondria also play an important role in apoptotic cell death. When it comes to apoptosis of mitochondrion, mitochondrial outer membrane permeabilization (MOMP) is commonly known to cause cell death. As a downstream pathological process of apoptotic signaling, MOMP participates in the leakage of cytochrome-c from mitochondrion to the cytosol and subsequently activate caspase proteases. Hence, targeting MOMP for the sake of manipulating cell death presents potential therapeutic effects among various types of diseases, such as autoimmune disorders, neurodegenerative diseases, and cancer. In this review, we highlights the roles and significance of mitochondria in pyroptosis to provide unexplored strategies that target the mitochondria to regulate cell death for clinical benefits.

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Hypercapnia promotes microglial pyroptosis via inhibiting mitophagy in hypoxemic adult rats

Cited by 24 publications

References 45 publications

Human Umbilical Cord Mesenchymal Stem Cell‐Derived Exosomes Attenuate Oxygen‐Glucose Deprivation/Reperfusion‐Induced Microglial Pyroptosis by Promoting FOXO3a‐Dependent Mitophagy

Human Umbilical Cord Mesenchymal Stem Cell‐Derived Exosomes Attenuate Oxygen‐Glucose Deprivation/Reperfusion‐Induced Microglial Pyroptosis by Promoting FOXO3a‐Dependent Mitophagy

Fisetin ameliorates cognitive impairment by activating mitophagy and suppressing neuroinflammation in rats with sepsis‐associated encephalopathy

The Role of Mitochondria in Pyroptosis

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