UC San Diego

TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is a transmembrane receptor that has recently been established as a key regulator of macrophages in multiple disease models. It is highly expressed in distinct macrophage populations in models of Alzheimer’s Disease, non-alcoholic steatohepatitis, and obesity. In this study, we interrogated the effect of deletion of TREM2 or treatment with a TREM2-activating antibody in myocardial injury models. To understand how TREM2 itself is regulated and how it mediates its effects on transcription, we established a conditionally immortalized monocyte progenitor cell line that constitutively expresses Cas9 and is able to differentiate into macrophages. We used this cell line to delete the intergenic enhancer of TREM2 and to knock out TREM2 as well as transcription factors. Thereby, we identified transcription factors mediating the effects of TREM2 on gene expression. Overall, in this work we demonstrate the role of TREM2 in myocardial injury, interrogate regulation of Trem2 expression, and identify transcription factors downstream of TREM2 signaling.