Abstract 9: Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) deficiency Attenuates Phagocytic Activities of Microglia and Exacerbates Ischemic Damage in Experimental Stroke
Clearing cellular debris after brain injury represents an important mechanism to re-attain tissue homeostasis and promote functional recovery. Triggering receptor expressed by myeloid cells-2 (TREM2) is involved in the innate immune system, and carries out surveillance functions by binding and phagocytosing pathogens. TREM2 is expressed on macrophages and microglia, and promotes the phagocytosis of apoptotic brain cells. Deficiency of functional TREM2 leads to accelerated dementia, and mutations in the TREM2 gene have been linked to Alzheimer’s. Here we explore the significance of TREM2 in a in-vitro and in-vivo stroke model. Cultures of neurons and microglia were subjected to OGD. TREM2-knockout (KO) and wildtype (WT) mice were subjected to permanent distal middle cerebral artery occlusion ischemic model. TREM2 knockdown in microglia by siRNA led to decreased transformation to an amoeboid morphology following co-culture and OGD exposure, but no effect on overall neuron death. OGD-exposed and nuclear lysates from neurons led to TREM2 signaling. In vivo, phagocytosis and infarcted brain tissue resorption was observed in wild-type mice by 14d, but no phagocytosis and little infarcted brain resorption was seen in TREM2 KO mice (p < 0.01)(Fig). TREM2 KO mice also had worsened neurological recovery (p < 0.05), and decreased viable brain tissue in the ipsilateral hemisphere. Numbers of activated microglia and macrophages in KO mice were decreased compared to WT, and oil red staining to identify foamy macrophages was nearly absent in the KO brains. These findings establish the relevance of TREM2 in phagocytosis of the infarcted brain and emphasize the importance of phagocytosis in neurological outcome following experimental stroke.
Author Disclosures: M. Kawabori: None. R. Kacimi: None. T. Kauppinen: None. C. Calosing: None. J. Kim: None. C. Christine: None. M. Nakamura: None. M. Yenari: None.
- © 2014 by American Heart Association, Inc.