TREM2is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor

Abstract

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. We report here that TREM2 is a thyroid hormone regulated gene and its expression in macrophages and microglia is stimulated by thyroid hormone. Both endogenous thyroid hormone and sobetirome, a synthetic thyroid hormone agonist drug, suppress pro-inflammatory cytokine production from myeloid cells including macrophages that have been treated with the SARS-CoV-2 spike protein which produces a strong, pro-inflammatory phenotype. Thyroid hormone agonism was also found to induce phagocytic behavior in microglia, a phenotype consistent with activation of the TREM2 pathway. The thyroid hormone antagonist NH-3 blocks the anti-inflammatory effects of thyroid hormone agonists and suppresses microglia phagocytosis. Finally, in a murine experimental autoimmune encephalomyelitis (EAE) multiple sclerosis model, treatment with Sob-AM2, a CNS-penetrating sobetirome prodrug, results in increased Trem2 expression in disease lesion resident myeloid cells which correlates with therapeutic benefit in the EAE clinical score and reduced damage to myelin. Our findings represent the first report of endocrine regulation of TREM2 and provide a unique opportunity to drug the TREM2 signaling pathway with orally active small molecule therapeutic agents.

Thyroid Hormone Receptor Beta as Tumor Suppressor: Untapped Potential in Treatment and Diagnostics in Solid Tumors

“…TRβ-selective thyromimetics have been developed [ 100 , 101 , 102 , 103 ] and have been shown to elicit the same transcriptional response as T 3 [ 104 ]. These drugs have been shown to be effective for treatment of metabolic and neurodegenerative disorders in clinical trials and to subvert the negative side-effects of hyperthyroidism [ 105 ], but have not yet been explored as anti-tumor agents.…”

Thyroid dysfunction and Alzheimer's disease, a vicious circle

“…Preclinical research indicates that thyroid hormones block APP gene expression by reducing histone H3 acetylation and histone H3 lysine 4 methylation, and thus reduce βA formation ( 79 ). Regulation of TREM2 gene expression on microglia by thyroid hormones has also been demonstrated ( 80 ). If TREM2 dysfunction occurs, it may alter the response of microglia to βA and may be involved in the etiology of Alzheimer’s disease through immune and inflammatory pathways ( 81 ).…”