Immunoglobulin G exacerbates endothelial-microglial crosstalk, promoting secondary injury in high-altitude cerebral edema.

Hypobaric hypoxia (HH)-induced blood-brain barrier (BBB) disruption is a critical pathological event in high-altitude cerebral edema (HACE). However, the mechanistic role of extravasated immunoglobulin G (IgG) in this process remains insufficiently characterized. This study elucidates that leaked IgG actively contributes to neuroinflammation and BBB impairment under HH conditions, functioning beyond being a passive biomarker. Using both in vivo and in vitro models, we demonstrated that HH rapidly induces Caveolin-1-dependent transcytosis of IgG across endothelial cells as an early event, preceding the degradation of TJs. Internalized IgG activated NF-κB signaling in endothelial cells, leading to the downregulation of Claudin-5 and ZO-1 and promoting NLRP3 inflammasome assembly. Concurrently, extravasated IgG drove microglial polarization toward a pro-inflammatory M1 phenotype, marked by increased IL-1β expression and p65 phosphorylation. Inhibition of Caveolin-1 using methyl-β-cyclodextrin (MβCD) significantly reduced IgG uptake, suppressed endothelial inflammatory signaling, and attenuated microglial activation, thereby preserving BBB integrity. These findings support the "two-hit" model, in which Caveolin-1-mediated IgG transcytosis initiates a feed-forward loop of neuroinflammation and BBB disruption. Our results identify Caveolin-1 as a promising therapeutic target and provide mechanistic insights into HACE pathogenesis, offering a foundation for novel preventive and treatment strategies.