Abstract:
Fever and associated metabolic modifications are biologically conserved responses to infection, though mediated differently in homeothermic versus poikilothermic vertebrates. We have therefore investigated fever-mediated modulation of cellular metabolism and function of murine, avian and piscine macrophages upon microbial-inflammatory activation. Fever temperatures enhanced activation-induced nitric oxide (NO) production in macrophages of mouse, chicken and rainbow trout origin. However, fever-mediated modulation of protein synthesis and cellular metabolism differed between cells of the three species. Fever temperature enhanced protein synthesis and accelerated the metabolic enhancement seen in murine macrophages, but avian and piscine macrophages did not show as much enhancement. Further, activated mouse macrophages first increased and then reduced mitochondrial oxidative phosphorylation in favor of glycolysis, a shift mediated by NO, and fever temperatures increased the speed of this transition. Neither chicken nor rainbow trout macrophages showed these specific metabolic transitions upon activation, though they made NO. Interestingly, rainbow trout macrophages were far less dependent on glycolysis than on oxidative phosphorylation for ATP generation, compared to mouse or chicken cells. Thus, fever temperatures accelerated the kinetics of activation-mediated functional enhancement in macrophages from all three species tested, but metabolic changes were quite different in them. In mouse macrophages, global gene expression analysis showed that fever temperature alone changed the basal transcriptomic landscape widely, while activation-induced gene expression profiles showed much smaller and narrower changes. These results provide insights into the complex matrix of macrophage responses to fever.