The Effects of Fever on Macrophage Metabolism and Function in Young and Aged Cells

Abstract

Abstract Fever is an adaptive immune response to infections. With aging comes a rise in background inflammation that does not protect against infection. Here, we investigate the metabolism and function of macrophages at fever temperatures in a mouse cell line, in young and aged peritoneal resident macrophages, and bone marrow derived macrophages. Fever temperatures generally enhance macrophage functions although the effects are complex and dynamic. We show in the RAW264.7 murine cell line, that a raise in the baseline body temperature of 37°C to a fever temperature of 39°C increased the speed in which macrophages shift from mitochondrial oxidative phosphorylation to glycolysis. Driving this metabolic reprogramming, is the production of nitric oxide. There is also an increase in global protein synthesis and an increase in the mRNA for iNOS, the enzyme that produces NO and inflammatory cytokine production. The metabolic shift was measured via the oxygen consumption and the proton efflux rate over time. Cells were stimulated with lipopolysaccharide and/or interferon-gamma (IFNg). Our data also shows that tissue resident PRMs from aged mice exhibit a much stronger response to fever than those of young mice, while bone marrow derived microphages (BMDM) appeared to show a similar response to that of RAW264.7 cell line. However, with the addition of a cyclooxygenase2 inhibitor to block the production of prostaglandin E2, BMDMs of aged mice show an exaggerated increase in their response to LPS+IFNg activation. This work uncovers differences in fever responses between young and aged individuals that may explain the overall outcomes of the aged to infection. Arkansas Immunology Foundation