Assessment of neuroinflammation in the aging hippocampus using large-molecule microdialysis: Sex differences and role of purinergic receptors.

ABSTRACT

Aging is associated with an enhanced neuroinflammatory response to acute immune challenge, often termed "inflammaging." However, there are conflicting reports about whether baseline levels of inflammatory markers are elevated under ambient conditions in the aging brain, or whether such changes are observed predominantly in response to acute challenge. The present studies utilized two distinct approaches to assess inflammatory markers in young and aging Fischer 344 rats. Experiment 1 examined total tissue content of inflammatory markers from hippocampus of adult (3 month), middle-aged (12 month), and aging (18 month) male Fischer (F) 344 rats using multiplex analysis (23-plex). Though trends emerged for several cytokines, no significant differences in basal tissue content were observed across the 3 ages examined. Experiment 2 measured extracellular concentrations of inflammatory factors in the hippocampus from adult (3 month) and aging (18 month) males and females using large-molecule in vivo microdialysis. Although few significant aging-related changes were observed, robust sex differences were observed in extracellular concentrations of CCL3, CCL20, and IL-1α. Experiment 2 also evaluated the involvement of the P2X7 purinergic receptor in neuroinflammation using reverse dialysis of the selective agonist BzATP. BzATP produced an increase in IL-1α and IL-1ß release and rapidly suppressed the release of CXCL1, CCL2, CCL3, CCL20, and IL-6. Other noteworthy sex by aging trends were observed in CCL3, IL-1ß, and IL-6. Together, these findings provide important new insight into late-aging and sex differences in neuroinflammation, and their regulation by the P2X7 receptor.