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NLRP3-GSDMD-dependent IL-1β Secretion from Microglia Mediates Learning and Memory Impairment in a Chronic
Chaohong Li1, Zhen Zhao2, Jiahao Jin2
1Henan Key Laboratory of Neurorestoratology, Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan, China; Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400000, China.
Abstract:
Hypoxia/reoxygenation caused by chronic intermittent hypoxia (CIH) plays an important role in cognitive deficits in patients with obstructive sleep apnea. However, the precise underlying mechanism remains unclear. This study investigated whether the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is involved in CIH-induced spatial learning and memory impairment in mice, and the possible underlying upstream and downstream mechanisms. The C57BL/6 male mice were exposed to CIH (21% O2-6% O2, 4 min/cycle, 8 h/day) for 9 weeks to investigate the role of NLRP3 in CIH-induced spatial learning and memory impairment in mice. BV2 cells were exposed to intermittent hypoxia (21% O2-1% O2, 90 min/cycle) for 48 h to investigate the possible mechanisms in vitro. We found that: 1) inhibition of NLRP3 inflammasome activation improved CIH-induced spatial learning and memory impairment in mice. 2) CIH damaged hippocampal neurons but increased the number of microglia in mice hippocampi; CIH activated microglia-specific NLRP3 inflammasome, leading to upregulation of matured IL-1β and N-GSDMD. 3) intermittent hypoxia activated NLRP3 inflammasome via the ROS-NF-κB signaling pathway to promote the release of matured IL-1β from microglia in a GSDMD-dependent manner without pyroptosis. 4) The IL-1β released from microglia might impair the synaptic plasticity of hippocampal CA3-CA1 synapses by acting on IL-1 receptors in hippocampal neurons. Our findings reveal that ROS-NF-κB-NLRP3 inflammasome-GSDMD dependent IL-1β release from microglia may participate in CIH-induced spatial learning and memory impairment by acting on hippocampal neuronal IL-1 receptor, leading to synaptic plasticity impairment.
Insights
Chronic intermittent hypoxia impairs memory by activating the NLRP3 inflammasome in microglia. Inhibiting this pathway improves cognitive function in mice with sleep apnea.
Area of Science:
- Neuroscience
- Immunology
- Sleep Medicine
Background:
- Chronic intermittent hypoxia (CIH) is linked to cognitive deficits in obstructive sleep apnea.
- The exact mechanisms behind CIH-induced cognitive impairment, particularly spatial learning and memory deficits, are not fully understood.
- The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a key regulator of inflammation.
Purpose of the Study:
- To investigate the role of the NLRP3 inflammasome in CIH-induced spatial learning and memory impairment in mice.
- To elucidate the upstream and downstream molecular mechanisms involved in this process.
Main Methods:
- Mice were exposed to chronic intermittent hypoxia (CIH) for 9 weeks.
- BV2 microglial cells were subjected to intermittent hypoxia in vitro.
- Investigated NLRP3 inflammasome activation, microglial changes, IL-1β release, and synaptic plasticity.
Main Results:
- Inhibition of NLRP3 inflammasome activation ameliorated CIH-induced spatial learning and memory deficits.
- CIH activated the NLRP3 inflammasome in microglia, increasing IL-1β and N-GSDMD levels.
- The ROS-NF-κB pathway mediated NLRP3 inflammasome activation, leading to GSDMD-dependent IL-1β release without pyroptosis.
Conclusions:
- The ROS-NF-κB-NLRP3 inflammasome-GSDMD pathway in microglia contributes to CIH-induced cognitive impairment.
- Microglial IL-1β release impairs hippocampal CA3-CA1 synaptic plasticity via neuronal IL-1 receptors.
- Targeting the NLRP3 inflammasome may offer a therapeutic strategy for cognitive deficits associated with sleep apnea.
