Abstract 73: Triggering Receptor Expressed on Myeloid Cells-2 Expression derived From Microglia Contributes to Neurological Recovery in Experimental Ischemic Stroke

Abstract

Background and Purpose: We previously reported that triggering receptor expressed on myeloid cells-2 (TREM2) expression promotes post-ischemic phagocytosis and leads to neurological recovery. However, the precise underlying mechanism is not fully understood yet. In present study, we aimed to clarify which pool of myeloid cells (brain resident microglia versus macrophage derived from circulation) are contributing to its beneficial role in post-ischemic recovery, with the usage of bone marrow (BM) chimeric mice. Methods: BM chimeric mice were created by BM transplanting BM from TREM2 knockout (KO) and wild type (Wt) mice into KO and Wt recipient mice. Thus, 4 groups (Wt (donor) to Wt (recipient), KO to Wt, Wt to KO, KO to KO; n=6/each) of BM chimeric mice were produced, then were subjected to dMCAO surgery. Neurological function was observed until 14 days after surgery. Infarct volume and immunohistological analysis (myeloid cell activation and infiltration: isolectin B4 (IB4) and CD11b; phagocytosis: oil red o and CD68; TREM2 expression) was also undergone. Results: Compared to mice lacking brain TREM2 (WT to KO and KO to KO), mice with intact TREM2 in brain microglia (KO to WT and WT to WT) showed better neurological recovery (p<0.05), and smaller infarct volume (p<0.01). Myeloid cell activation and infiltration (IB4) was significantly decreased in order of WT to WT, KO to Wt, Wt to KO, KO to KO (p<0.05). Likewise, number of TREM2 positive myeloid cells (CD11b) showed similar decreases. Oil red o staining demonstrated that mice with intact TREM2 in microglia (KO to WT and WT to WT) showed more accumulation of foamy macrophages, compared to mice lacking TREM2 in brain (Wt to KO and KO to KO). Furthermore, both the number and proportion of TREM2 positive phagocytes (CD68) was significantly higher in mice with intact TREM2 in the brain, compared to mice lacking brain TREM2. Conclusions: Although our results suggest TREM2 expression in both microglia and circulating macrophage were crucial for post-ischemic recovery, its beneficial effect was greater when TREM2 was present in brain resident microglia.