Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor on macrophages and microglia that senses and responds to disease-associated signals to regulate the phenotype of these innate immune cells. The TREM2 signaling pathway has been implicated in a variety of diseases ranging from neurodegeneration in the central nervous system to metabolic disease in the periphery. Here, we report that TREM2 is a thyroid hormone-regulated gene and its expression in macrophages and microglia is stimulated by thyroid hormone and synthetic thyroid hormone agonists (thyromimetics). Our findings report the endocrine regulation of TREM2 by thyroid hormone, and provide a unique opportunity to drug the TREM2 signaling pathway with orally active small-molecule therapeutic agents. Display omitted •TREM2 is regulated by thyroid hormone (T3) and thyromimetics•T3 and thyromimetics produce anti-inflammatory effects in microglia and macrophages•T3 and thyromimetics induce phagocytosis in microglia•EAE mice treated with T3 or thyromimetic present with reduced clinical scores In this article, Ferrara et al. show that an important immune system signaling hub, TREM2, is transcriptionally regulated by thyroid hormone. This renders TREM2 druggable by small-molecule synthetic thyroid hormone derivatives, which impart beneficial phagocytic and anti-inflammatory properties in relevant cell types and disease model mice.