The goal of this research is to develop new therapeutic approaches to treating inflammatory diseases such as neurodegeneration, metabolic disease, and acute critical illness. These seemingly dissimilar disorders are linked by the biology of thyroid hormone action and TREM2. Triggering receptor expressed on myeloid cells (TREM2) is a cell surface receptor expressed on macrophages and microglia that coordinates the inflammatory response in these innate immune system cells. Signaling through the TREM2 pathway transitions macrophages and microglia from a pro-inflammatory to an anti-inflammatory, restorative, injury-resolving phenotype. Loss of function mutations in TREM2 are associated with risk of developing neurodegenerative and metabolic disease providing a critical human genetics precedent to the health importance of the TREM2 pathway and properly functioning macrophages and microglia. TREM2 is considered an “undruggable” or difficulty to drug target for therapeutic intervention because its activating ligands are heterogenous cell damage associated lipids and lipoprotein particles rather than a single molecule ligand. We discovered recently that TREM2 is a thyroid hormone regulated gene and treatment of cells or mice with small molecule thyroid hormone agonists called thyromimetics stimulates expression of TREM2 and increases flux through the TREM2 signaling pathway. This effectively makes TREM2 druggable using small molecules with excellent drug-like properties. We are now uniquely positioned to explore the outcomes of thyromimetic TREM2 pathway activation in both the CNS and periphery. In prior research we discovered and developed the peripherally acting thyroid hormone agonist sobetirome, as well as a prodrug version called Sob-AM2 that is converted to sobetirome in the CNS by fatty acid-amide hydrolase (FAAH) thereby increasing CNS sobetirome exposure while minimizing exposure in the periphery. The research plan is organized around three specific aims that test the hypothesis of thyroid hormone induced TREM2 activation in models of demyelinating neuro-inflammation, chronic peripheral inflammation leading to fibrosis, and acute viral and bacterial induced hyper-inflammation leading to cytokine storm and multi-organ failure. These studies will lay the foundation for development of a new class of drugs with the unique and powerful ability to transition a pro-inflammatory innate immune response to a resolving, restorative, wound healing response in both the CNS and periphery.