Sex effects of Interleukin-6 deficiency on neuroinflammation in aged C57Bl/6 mice

Abstract

High levels of Interleukin-6 (IL-6) are associated with an increased risk of dementia in the elderly and can increase neuroinflammation in mice. Dementia is more frequent in females, and IL-6 is regulated by estrogen, suggesting that elevated IL-6 levels may contribute to neuroinflammation and dementia particularly in women. Therefore we hypothesized that IL-6 deficient ( −/−) female mice would have lower aging-related neuroinflammation than wild type (WT). We quantified neuroinflammatory markers which are affected by aging, and regulated by both estrogen and IL-6; glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), interferon gamma (IFNγ), lipid peroxidation (MDA), and synaptic density (SNAP25) and in IL-6 −/− and WT C57Bl/6 mice. To determine age effects we used mid-age (18 months) and old-age (24 months) mice, and to determine region specific effects we used the hippocampus which is impaired in dementia and the cerebellum which is unimpaired in dementia. Unexpectedly, there were no effects of IL-6 deficiency on GFAP, MDA or SNAP25 levels in females, but IL-6 deficiency was associated with lower cerebellar MBP ( p < 0.05) levels. Interestingly, the old-aged IL-6 −/− males had higher GFAP and MDA levels ( p < 0.05) in both the hippocampus and cerebellum, in addition to a greater body weight than WT. We suggest that IL-6 is important for promoting myelin synthesis in aged females, and that drugs which inhibit the synthesis of IL-6 in males may inadvertently affect fatty acid metabolism and augment aging-related neuroinflammation.