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Na+/K+-ATPase (NKA) plays an important role in the central nervous system. However, little is known about its function in the microglia. Here, we found that NKAα1 forms a complex with the purinergic P2X7 receptor (P2X7R), an adenosine 5′-triphosphate (ATP)-gated ion channel, under physiological conditions. Chronic stress or treatment with lipopolysaccharide plus ATP decreased the membrane expression of NKAα1 in microglia, facilitated P2X7R function, and promoted microglia inflammatory activation via activation of the NLRP3 inflammasome. Accordingly, global deletion or conditional deletion of NKAα1 in microglia under chronic stress-induced aggravated anxiety-like behavior and neuronal hyperexcitability. DR5-12D, a monoclonal antibody that stabilizes membrane NKAα1, improved stress-induced anxiety-like behavior and ameliorated neuronal hyperexcitability and neurogenesis deficits in the ventral hippocampus of mice. Our results reveal that NKAα1 limits microglia inflammation and may provide a target for the treatment of stress-related neuroinflammation and diseases.
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•NKAα1 forms a complex with P2X7R, which regulates ATP-dependent microglia activation•Membrane NKAα1 loss facilitates P2X7R-mediated K+ efflux in microglia•Microglial NKAα1 deficiency exacerbates neuronal excitability and anxiety behavior•DR5-12D alleviates anxiety through stabilizing microglia membrane NKAα1
While Na+/K+-ATPase (NKA) plays important roles in the CNS, its role in microglia is unclear. Huang et al. find that NKAα1 inhibits microglia activation by forming a complex with P2X7R. Stress decreases membrane expression of NKAα1, facilitating P2X7R-mediated K+ efflux and inflammation. DR5-12D prevents inflammation by stabilizing membrane NKAα1, indicating that NKAα1 may be a target for stress-induced anxiety disorders.