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High-altitude cerebral hypoxia (HACE) is a fatal acute mountain sickness (AMS).Publications implicate hypoxia-elicited inflammation, but if it correlates to HACE remains unclear.We have reported that CRHR1 is involved.Here we report systemic inflammation facilitates HACE.Rapidly ascend to high-altitude increases plasma IL-1β and TNF-α, and CRH levels in volunteers, which correlates with AMS.Rats studies showed these effects were reversed by DEX.By mimic altitude, single LPS or hypoxia could not cause brain edema, while did the LPS and followed by hypoxia.Cytokines activate AQP4/AQP4mRNA via TLR4-initiated AMPK and NF-kB and increases water permeability in astrocytes.Hypoxia activates microglia releasing cytokines via activating CRH/CRHR1, and induce extracellular hypoosmolarity by reduced Na+-K+-ATPase.Conclusion: hypoxia induces the inflammation, which correlates with AMS occurrence and CRH activation.Pro-inflammatory factors release from CRH-elicited microglia and peripheral sites, that plus Na+-K+-ATPase dysfunction facilitate HACE.CRHR1 is a molecular target for HACE.