Astrocyte immunosenescence and deficits in interleukin 10 signaling in the aged brain disrupt the regulation of microglia following innate immune activation.

Microglia, the innate immune cells of the brain, develops a pro-inflammatory, "primed" profile with age. Using single-cell RNA-sequencing, we confirmed hippocampal microglia of aged mice (18 m.o.) had an amplified (4 h) and prolonged (24 h) neuroinflammatory response to peripheral lipopolysaccharide (LPS) challenge compared to adults (2 m.o.). Overall, there were several unique cell-, age-, and time-dependent differences in the clusters of microglia identified. Analysis of upstream regulators and canonical pathways revealed impaired regulation of an activated, neuroinflammatory state within microglia. Moreover, microglia in the aged hippocampus failed to turn over during the resolving phase of neuroinflammation. Concomitantly, astrocytes in the aged hippocampus were "immunosenescent" both 4 and 24 h after LPS challenge. For example, aged astrocytes had reduced anti-inflammatory signaling and cholesterol biosynthesis, two pathways by which astrocytes regulate the inflammatory profile of microglia. One of the pathways reduced in the aged hippocampus was interleukin (IL)-10 signaling. This pathway increases astrocytic expression of transforming growth factor (TGF)-ß, an anti-inflammatory cytokine with abundant receptor expression on microglia. Therefore, transgenic astrocytic Il10raKO mice were generated to determine if impaired IL-10R/TGFß signaling within astrocytes caused an amplified microglial neuroinflammatory response. Astrocytic Il10raKO caused exaggerated sickness behavior and a prolonged neuroinflammatory response to peripheral LPS, including increased social avoidance with amplified microglial Il1b and Tnf mRNA expression. In summary, astrocytes had an immunosenescent profile with age and, in response to peripheral LPS, had IL-10R signaling deficits and a lack of cholesterol biosynthesis, both leading to the inability to resolve microglial activation.

Assessment of Gender Disparities in Short-Term and Long-Term Outcomes Following Posterior Fossa Tumor Resection.

Introduction The analysis of social determinants of health (SDOH) across different surgical populations is critical for the identification of health disparities and the development risk mitigation strategies among vulnerable patients. Research into the impact of gender on neurosurgical outcomes remains limited. The aim of the present study was to assess the effect of gender on outcomes, in a matched sample, following posterior fossa tumor resection, a high-risk neurosurgical procedure. Methods Two hundred seventy-eight consecutive patients undergoing posterior fossa tumor resection over a six-year period (June 07, 2013, to April 29, 2019) at a single academic medical system were retrospectively evaluated. Short-term outcomes included 30- and 90-day rates of emergency department (ED) visit, readmission, reoperation, and mortality. Long-term outcomes included mortality and reoperation for the duration of follow-up. Firstly, male and female patients in the entire pre-match sample were compared. Thereafter, coarsened exact matching was employed to control for confounding variables, matching male and female patients on key demographic factors - including history of prior surgery, median household income, and race, amongst others - and outcome comparison was repeated. Results In both the entire pre-match sample and matched cohort analyses, no significant differences in adverse postsurgical events were discerned between the female and male patients when evaluating 30-day or 90-day rates of ED visit, readmission, reoperation, and mortality. There were also no differences in reoperation or mortality for the duration of follow-up. Conclusion Gender does not appear to impact short- or long-term outcomes following posterior fossa tumor resection. As such, risk assessment and mitigation strategies in this population should focus on other SDOH. Further studies should assess the role of other SDOH within this population.