fig2

Figure 2. Two-step activation of DAM. Homeostatic microglia are differentiated into the DAM phenotype via a sequential two-step process. It begins with TREM2 independent change to an intermediate state. The cause of this initial change is not well known, but it is marked by the downregulation of homeostatic genes such as purinergic receptor P2RY12 and transmembrane protein 119 (Tmem119). This intermediate state is then activated to the DAM phenotype through a TREM2 signal-dependent second step involving the upregulation of many genes, such as those involved in phagocytosis (TREM2, Axl), lipid metabolism (APOE, Lpl), and inflammation (IL-1β), among others. APOE: Apolipoprotein E; Axl: Axl receptor tyrosine kinase; Cst7: cystatin F; Hexb: hexosaminidase subunit beta; Itgax: integrin subunit alpha X (also known as CD11c); Lpl: lipoprotein lipase; P2RY12: purinergic receptor P2Y12; Tgfbr1: transforming growth factor beta receptor 1; Tmem119: transmembrane protein 119; TREM2: triggering receptor expressed on myeloid cells 2.