Burns are more than skin deep: Heightened neuroinflammation after cutaneous injury in aged mice

Abstract

Abstract By 2050, 1 in 6 people will be 65 or older. As the aging population grows so too does the importance of understanding how injuries in this age group lead to a greater incidence of neurological complications and mortality. Neurological complications may be driven by elevated pro-inflammatory cytokines and astrocyte activation within the hippocampus (HPC), which reduces levels of phosphorylated cyclic-AMP response binding element (pCREB), leading to cognitive decline and memory impairment. To examine the effects of injury on neuroinflammation in advanced age, young and aged mice were anesthetized and subjected to a 15% total body surface area scald or sham injury. As an index of neuroinflammation, we observed an 85-fold (p<0.05) increase in ccl2 and a 35-fold (p=0.05) elevation in tnfa 24 hours post injury in the brains of aged mice compared to young groups and aged sham mice. We also saw a 13-fold (p<0.05) increase in ccl2 within isolated hippocampus of aged injured mice, when compared to aged shams. Interestingly, when investigating specific HPC regions, immunofluorescence staining showed a 20% rise (p<0.05) in glial fibrillary acidic protein (GFAP) positive astrocytes within the cornu ammonis 3 (CA3) of aged injured mice when compared to sham groups. GFAP+ astrocytes are associated with neurotoxicity and cognitive decline. Finally, there was a 20% decrease (p<0.05) in pCREB staining by immunohistochemistry in the dentate gyrus of aged mice compared to young regardless of injury. These data suggest that remote injury in aged, but not young mice, causes neuroinflammation and astrocyte activation, which paired with an age related reduction in pCREB, could contribute to cognitive decline. Supported in part by NIH R01 AG018859 (EJK), R35 GM131831 (EJK), T32 AG000279 (KLM), and K08 134185 (JPI)