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

Cell Chem Biol. 2022 Feb 17;29(2):239-248.e4. doi: 10.1016/j.chembiol.2021.07.014. Epub 2021 Aug 9.

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. 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.

Keywords: SARS-CoV-2; TREM2; innate immunity; neurodegeneration; therapeutics; thyroid hormone.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / chemical synthesis
  • Acetates / pharmacology*
  • Animals
  • Binding Sites
  • Brain / drug effects
  • Brain / immunology
  • Brain / pathology
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Gene Expression Regulation
  • Humans
  • Immunity, Innate
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / pathology
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Microglia / drug effects*
  • Microglia / immunology
  • Microglia / pathology
  • Models, Molecular
  • Phenols / chemical synthesis
  • Phenols / pharmacology*
  • Phenoxyacetates / pharmacology
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / genetics
  • RNA, Messenger / immunology
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Immunologic / genetics*
  • Receptors, Immunologic / immunology
  • Response Elements
  • Retinoid X Receptors / chemistry
  • Retinoid X Receptors / genetics*
  • Retinoid X Receptors / metabolism
  • Signal Transduction
  • Thyroid Hormones / pharmacology*

Substances

  • (4-(4-hydroxy-3-isopropyl-5-(4-nitrophenylethynyl)benzyl)-3,5-dimethylphenoxy)acetic acid
  • Acetates
  • GC 1 compound
  • Membrane Glycoproteins
  • Phenols
  • Phenoxyacetates
  • RNA, Messenger
  • Receptors, Immunologic
  • Retinoid X Receptors
  • Thyroid Hormones
  • Trem2 protein, mouse