The effect of increasing levels of hyperthermia on autophagy and cellular stress in peripheral blood mononuclear cells from young adults

Exposure to an elevated state of hyperthermia is associated with heat-induced cytotoxicity, which if left unabated, can cause tissue damage and death. While activation of autophagy is vital to counter heat-induced cellular injury and promote cellular survival, the dose-dependent autophagic response to controlled elevations in body core temperature have yet to be evaluated in an in vivo human model. Therefore, on separate days we evaluated cellular responses in 12 young adults (mean [SD]: 22 [2] years; 6 women) who were immersed (up to the clavicle) in water set at a temperature to clamp core temperature (esophageal) at either baseline resting (control; 37°C), moderate (38°C), or hot (39°C) conditions for 60-min. Autophagy was characterized in peripheral blood mononuclear cells before and after water immersion, as well as following 3h of seated recovery in a temperate environment (~22°C). Proteins associated with autophagy and cellular stress pathways (apoptosis, inflammation, heat shock response) were assessed via Western blot. With increasing levels of hyperthermia, we observed increasing autophagic activation (as indexed via elevated LC3-II and decreasing p62) at end-exposure to moderate and hot core temperature clamps, with evidence of elevated autophagic activity up to 3h after exposure to the hot condition. This was paired with significant end-exposure elevations in cellular stress proteins including cleaved-caspase-3, TNF-α, and IL-6 in the hottest condition. Taken together, our findings suggest autophagy is activated with increasing levels of hyperthermia and may be important in restoring cellular homeostasis when exposed to body core temperatures above 38°C in healthy young adults.