Inhibition of TXNIP/NLRP3/GSDMD Pathway and Antioxidant Therapy Mitigate Cognitive Dysfunction Induced by Chronic Intermittent Hypoxia

Aims: Mitochondrial homeostasis is essential for maintaining central nervous system function. Both inflammation and oxidative stress induced by chronic intermittent hypoxia (CIH) can result in neuronal mitochondrial injury in obstructive sleep apnea syndrome (OSAS)-related cognitive dysfunction. Recent evidence implicates neuronal impairment caused by abnormal activation of microglia as a key contributor to CIH-induced cognitive dysfunction. However, the mechanism between microglia and neuronal injury remains elusive. This study seeks to elucidate the underlying mechanism of microglia-mediated neuronal injury in CIH-induced cognitive dysfunction. Results: Both the levels of pro-inflammatory factors and reactive oxygen species (ROS) were elevated; neuronal mitochondrial and cytomembrane injury and neuronal pyroptosis also occurred in CIH models in vitro and in vivo . Microglial cells RNA sequencing data revealed that CIH upregulated the nucleotide-binding and oligomerization domain–like receptor pathway, and in vitro experiments confirmed that the thioredoxin-interacting protein (TXNIP)/nucleotide-binding and oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3)/gasdermin D (GSDMD) pathway modulated inflammation and oxidative stress in BV-2 cells and regulated neuronal mitochondrial and cytomembrane injury and pyroptosis. Co-immunoprecipitation results verified that TXNIP bound directly to NLRP3 in BV-2 cells. Furthermore, GSDMD-derived inhibitor (Ac-FLTD-CMK) abolished the elevation in inflammation and oxidative stress markers induced by TXNIP overexpression after CIH exposure. In addition, it alleviated HT-22 cells’ mitochondrial and cytomembrane injury and suppressed the activation of TXNIP/NLRP3/GSDMD pathway in BV-2 cells induced by CIH after the application of mitochondrial antioxidant Mito-TEMPO to BV-2 cells, thereby mitigating microglia-mediated neuronal pyroptosis. These findings were corroborated by in vivo experiments. Innovation and Conclusion: These results reveal that microglial TXNIP/NLRP3/GSDMD pathway activation is a key mechanism linking CIH to neuronal injury in OSAS-related cognitive dysfunction. Inhibition of TXNIP/NLRP3/GSDMD pathway and antioxidant therapy could protect against CIH-induced cognitive dysfunction by ameliorating the damaging effects of cytokines of inflammation and oxidative stress from microglia, while preventing neuronal mitochondrial and cytomembrane injury and pyroptosis. This work identifies a promising target for pharmacological intervention in OSAS-related cognitive dysfunction. Antioxid. Redox Signal. 44, 373–392.