Temperature accelerates and enhances metabolic alterations of stimulated macrophages

Fever is an innate immune response to infection that is useful beyond its ability to reduce bacterial and viral replication. Adherent cells were plated with a density of 5.3x105/cm2 and treated with either 100ng/ml LPS, 50ng/ml IFNg or a combination of both. Cells were incubated over a 400-minute period. Incubation of macrophages at 39°C compared to 37°C increased ATP production overall. Upon stimulation, macrophages alter their metabolism from partly respirative to almost entirely glycolytic within 5 hours with strong stimuli like LPS + IFGg. Weaker stimuli such as either treatment alone took longer. When exposed to various temperatures above baseline, this metabolic reprogramming intensifies, accelerates, and is accompanied by further increases in pro-inflammatory cytokines and nitric oxide (NO). Highly dependent on cell density, the reprogramming response is driven by NO production that is blocked by aminoguanidine. Metabolism and metabolic reprogramming gradually increased with temperature [tested in +0.5°C increments between 37°C and 39°C]. Differences in overall metabolism and metabolic reprogramming were also observed between peritoneal resident macrophages and bone marrow derived macrophages of young and aged mice at fever temperatures.