Temperature-induced membrane trafficking drives antibody delivery to the brain

AbstractDespite quotidian occurrence of fever and hyperthermia, cell biological mechanisms underlying their effects remain unclear. Neurological complications of severe (>40°C) fever have been associated with increased blood-brain barrier (BBB) permeability due to structural disruption, while little is known about brain physiology of moderate fever. Here, we show that a temperature increase to 39-40°C increased fluid-phase uptake in PC12 cells and primary neurons. Uptake of selective cargoes showed that clathrin-mediated endocytosis and macropinocytosis were induced in a translation-dependent manner, consistent with a role for heat shock response. Exocytic recycling was also increased by hyperthermia, suggesting a comprehensive boost of membrane trafficking. Mild (<39°C) whole-body hyperthermiain vivotriggered fluid-phase uptake in various organs, notably enabling brain accumulation of an intravenously injected antibody that was blocked by dynamin inhibition. Taken together, our findings show that fever systemically regulates membrane trafficking, reveal dynamin-dependent endocytosis as a cell biological mechanism for temperature control of BBB permeability, and demonstrate a clinical potential of mild hyperthermia for facilitating brain delivery of biologic drugs.HighlightsTemperature increase of 2-3°C upregulates endocytosis and exocytosisTemperature-induced upregulation of membrane trafficking requires protein translation and dynamin functionMild whole-body hyperthermia enhances fluid-phase endocytosis across the bodyMild hyperthermia enables delivery of an exogenous antibody from the bloodstream into the brain through a dynamin-dependent pathway