TREM2 is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor
| Autor: | Priya Chaudhary, Thomas S. Scanlan, Edvinas Pocius, Brooke A. Napier, Gail Marracci, Hannah Miller, Skylar J. Ferrara, Evan Calkins, Dennis Bourdette, Margaret J. DeBell, Ben Emery |
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| Rok vydání: | 2022 |
| Předmět: |
Models
Molecular Protein Conformation alpha-Helical Clinical Biochemistry Acetates Phenoxyacetates Biochemistry Mice Drug Discovery Sobetirome Receptors Immunologic Promoter Regions Genetic Receptor Membrane Glycoproteins Microglia Experimental autoimmune encephalomyelitis Thyroid Brain medicine.anatomical_structure Molecular Medicine Signal transduction Protein Binding Signal Transduction Thyroid Hormones Encephalomyelitis Autoimmune Experimental Biology Response Elements Article Phenols medicine Animals Humans Protein Interaction Domains and Motifs RNA Messenger Molecular Biology Pharmacology Binding Sites Thyroid hormone receptor Innate immune system business.industry TREM2 Macrophages medicine.disease Immunity Innate Mice Inbred C57BL Retinoid X Receptors Gene Expression Regulation Cancer research Protein Conformation beta-Strand business Hormone |
| Zdroj: | Cell Chem Biol bioRxiv |
| ISSN: | 2451-9456 |
| DOI: | 10.1016/j.chembiol.2021.07.014 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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