Influence of Age and Sex on microRNA Response and Recovery in the Hippocampus Following Sepsis

Sepsis, defined as a life-threatening organ dysfunction caused by a dysregulated host immune response to infection, is a common and dangerous clinical syndrome. Sepsis results in an excessive host inflammatory response that can induce immediate and persistent cognitive decline, and this is known to be worse in older individuals. Sex-specific differences in the outcome of infectious diseases and sepsis appear to favor females. These differences likely involve sex steroids, sex chromosomes, and possibly epigenetic mechanisms. We employed a murine model to examine the influence of age and sex on the brain's microRNA (miR) response following sepsis. Young (~ 4 months) and old (~ 20 months) adult mice (C57BL/6) of both sexes underwent cecal ligation and puncture (CLP) with daily restraint stress. Differential expression of hippocampal miR was examined in age- and sex-matched controls at 1 and 4 days post-CLP. A sexually dimorphic miR response was observed. Similar to previous work examining the transcription profile, young females exhibited a better recovery of the miR profile from day1 to day4, relative to young males and old females. For young males and all female groups, the initial response mainly involved a decrease in miR expression. In contrast, old males exhibited only upregulated miR on day1 and day4, with 22 miR upregulated across days. Examination of the relationship of these 22 upregulated miR with mRNA expression indicated downregulation of mRNA with time from induction of sepsis and was more pronounced for mRNA that were associated with multiple upregulated miR. The results emphasize age and sex differences in epigenetic mechanisms that likely contribute sexually dimorphic responses to sepsis. Overall design: This study was conducted on 48 mice either 24 hours or 4 days after sepsis [young male control (n = 4), young male 24 hours post-sepsis (n = 4), young male 4 days post-sepsis (n = 4), old male control (n = 4), old male 24 hours post-sepsis (n = 4), old male 4 days post-sepsis (n = 4), young female control (n = 4), young female 24 hours post-sepsis (n = 4), young female 4 days post-sepsis (n = 4), old female control (n = 4), old female 24 hours post-sepsis (n = 4), and old female 4 days post-sepsis (n = 4)]. Hippocampal microRNA was used to investigate how sepsis altered the response in the brain within different age and sex groups.