Abstract 133: Triggering Receptor Expressed on Myeloid Cells-2 Improves Post-stroke Neurological Function and Regulates Microglia/Macrophage Phenotype in Aged Female Mice

Abstract

Background and Purpose: We previously reported that triggering receptor expressed on myeloid cells-2 (TREM2) expression on microglia/macrophage activates its phagocytic function and promotes stroke recovery. Although its importance has been demonstrated, it is unclear whether there is a similar effect in females. Furthermore, TREM2 mutations have been linked to dementia. In the present study, we explored the influence of TREM2 deficiency in aged female mice subjected to middle cerebral artery occlusion (MCAO). We assessed histology, sensorimotor and cognitive functions along with post stroke immune responses. Methods: Age matched (≥8months) female TREM2 knockout (TREM2-KO) and Wild type (Wt) mice were subjected to permanent distal MCAO. Sensorimotor and cognitive (Y-maze test) functions and infarct size were assessed up to 14d after stroke (n=6/each). Microglial activation (isolectin B4, IB4 & CD68), phagocytosis (oil red O stain) and M1 (NO/iNOS) and M2 (arginase, Arg) markers 1,3,7 and 14d post MCAO. Results: At baseline, aged female mice lacking TREM2 had similar cognitive & sensorimotor function. However, post stroke, TREM2-KO females, compared to Wt, showed worsened cognitive (p<0.01) and neurological function (p<0.05). Female TREM2 knockout mice also had larger infarct volumes (p<0.05) and reduced phagocytic activity (p<0.01). Microglia/macrophage accumulation, which peaked by 7d, was significantly inhibited in TREM2-KO mice (p<0.01). TREM2-KO mice also showed fewer CD68+ phagocytes; however, iNOS positive CD68 cells were significantly increased at days 3 & 7 (p<0.05), while, Arg positive CD68 cells was significantly decreased at days 7 & 14 (p<0.05) in the TREM2-KO group, compared to the Wt group and suggests a M2 bias for TREM2. Conclusions: Similar to male mice, TREM2 seems to have beneficial properties in female mice. TREM2 deficient female mice had larger infarct sizes and worsened neurological performance. Microglial responses also seemed to suggest that TREM2 promotes beneficial and/or recovery pathways.