NLRP3 Deficiency Protects Against Intermittent Hypoxia-Induced Neuroinflammation and Mitochondrial ROS by Promoting the PINK1-Parkin Pathway of Mitophagy in a Murine Model of Sleep Apnea.

Obstructive sleep apnea (OSA) associated neurocognitive impairment is mainly caused by chronic intermittent hypoxia (CIH)-triggered neuroinflammation and oxidative stress. Previous study has demonstrated that mitochondrial reactive oxygen species (mtROS) was pivotal for hypoxia-related tissue injury. As a cytosolic multiprotein complex that participates in various inflammatory and neurodegenerative diseases, NLRP3 inflammasome could be activated by mtROS and thereby affected by the mitochondria-selective autophagy. However, the role of NLRP3 and possible mitophagy mechanism in CIH-elicited neuroinflammation remain to be elucidated. Compared with wild-type mice, NLRP3 deficiency protected them from CIH-induced neuronal damage, as indicated by the restoration of fear-conditioning test results and amelioration of neuron apoptosis. In addition, NLRP3 knockout mice displayed the mitigated microglia activation that elicited by CIH, concomitantly with elimination of damaged mitochondria and reduction of oxidative stress levels (malondialdehyde and superoxide dismutase). Elevated LC3 and beclin1 expressions were remarkably observed in CIH group. In vitro experiments, intermittent hypoxia (IH) significantly facilitated mitophagy induction and NLRP3 inflammasome activation in microglial (BV2) cells. Moreover, IH enhanced the accumulation of damaged mitochondria, increased mitochondrial depolarization and augmented mtROS release. Consistently, NLRP3 deletion elicited a protective phenotype against IH through enhancement of Parkin-mediated mitophagy. Furthermore, Parkin deletion or pretreated with 3MA (autophagy inhibitor) exacerbated these detrimental actions of IH, which was accompanied with NLRP3 inflammasome activation. These results revealed NLRP3 deficiency acted as a protective promotor through enhancing Parkin-depended mitophagy in CIH-induced neuroinflammation. Thus, NLRP3 gene knockout or pharmacological blockage could be as a potential therapeutic strategy for OSA-associated neurocognitive impairment.

Wu X ，Gong L ，Xie L ，Gu W ，Wang X ，Liu Z ，Li S ... -  《Frontiers in Immunology》

PINK1-parkin pathway of mitophagy protects against contrast-induced acute kidney injury via decreasing mitochondrial ROS and NLRP3 inflammasome activation.

Contrast-induced acute kidney injury (CI-AKI) occurs in more than 30% of patients after intravenous iodinated contrast media and causes serious complications, including renal failure and mortality. Recent research has demonstrated that routine antioxidant and alkaline therapy failed to show benefits in CI-AKI patients with high risk for renal complications. Mitophagy is a mechanism of selective autophagy, which controls mitochondrial quality and mitochondrial reactive oxygen species (ROS) through degradation of damaged mitochondria. The role of mitophagy and its regulation of apoptosis in CI-AKI are poorly understood. In this study, we demonstrated that mitophagy was induced in renal tubular epithelial cells (RTECs) during CI-AKI, both in vivo and in vitro. Meanwhile, contrast media-induced mitophagy was abolished when silencing PINK1 or PARK2 (Parkin), indicating a dominant role of the PINK1-Parkin pathway in mitophagy. Moreover, mitochondrial damage, mitochondrial ROS, RTEC apoptosis, and renal injury under contrast exposure were more severe in PINK1- or PARK2-deficient cells and mice than in wild-type groups. Functionally, PINK1-Parkin-mediated mitophagy prevented RTEC apoptosis and tissue damage in CI-AKI through reducing mitochondrial ROS and subsequent NLRP3 inflammasome activation. These results demonstrated that PINK1-Parkin-mediated mitophagy played a protective role in CI-AKI by reducing NLRP3 inflammasome activation.

Lin Q ，Li S ，Jiang N ，Shao X ，Zhang M ，Jin H ，Zhang Z ，Shen J ，Zhou Y ，Zhou W ，Gu L ，Lu R ，Ni Z ... -  《Redox Biology》

Heterozygous SOD2 deletion deteriorated chronic intermittent hypoxia-induced lung inflammation and vascular remodeling through mtROS-NLRP3 signaling pathway.

Song JQ ，Jiang LY ，Fu CP ，Wu X ，Liu ZL ，Xie L ，Wu XD ，Hao SY ，Li SQ ... -  《-》

NLRP3 inflammasome mediates chronic intermittent hypoxia-induced renal injury implication of the microRNA-155/FOXO3a signaling pathway.

Chronic intermittent hypoxia (CIH), as the foremost pathophysiological change of obstructive sleep apnea (OSA), contributes to continued deterioration in renal function. Nucleotide-binding domain like receptor protein 3 (NLRP3) inflammasome is a multiprotein complex that triggers innate immune responses to infection and cell stress through activation of caspase-1 and maturation of inflammatory pro-interleukin-1β cytokine. Emerging evidence indicates that inhibition of the NLRP3 inflammasome ameliorates renal injury. Nevertheless, it is uncertain whether NLRP3 inflammasome participates in CIH-induced renal injury. The molecular mechanisms modulating NLRP3 inflammasome activation remain to be elucidated. Compared with wild-type mice, NLRP3 knockout mice dramatically protected them from kidney injury, as indicated by the restoration of creatinine levels, lessened histopathological alterations, and the suppression of macrophages infiltration stained with F4/80. NLRP3 deficiency notably reversed CIH-induced oxidative stress (malondialdehyde and superoxide dismutase), concomitantly with the abrogated apoptosis-related proteins and proinflammatory signaling pathway. Consistently, NLRP3-deficient tubular cells remarkably inhibited reactive oxygen species generation and NLRP3 inflammasome activation. Furthermore, our study revealed that microRNA-155 (miR-155) was augmented in the renal tissue and HK-2 cells exposed to CIH. In addition, we investigated the role of miR-155 in the regulation of NLRP3 inflammasome. Inhibition of miR-155 suppressed the CIH-induced NLRP3 inflammasome activation in renal tubular cells, whereas overexpression of miR-155 promoted oxidation and enhanced NLRP3 pathway. Collectively, we demonstrated that miR-155 might be a positive-regulator of NLRP3 pathway by inhibiting the targeted FOXO3a gene. These results established a link between the miR-155/FOXO3a pathway and the NLRP3 inflammasome, suggesting pharmacological blockage of NLRP3 as a potential therapeutic strategy for OSA-associated chronic kidney disease.

Wu X ，Chang SC ，Jin J ，Gu W ，Li S ... -  《-》

Pinocembrin ameliorates intermittent hypoxia-induced neuroinflammation through BNIP3-dependent mitophagy in a murine model of sleep apnea.

Gong LJ ，Wang XY ，Gu WY ，Wu X ... -  《Journal of Neuroinflammation》