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.
Subject(s)
Acetates/pharmacology , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Membrane Glycoproteins/genetics , Microglia/drug effects , Phenols/pharmacology , Receptors, Immunologic/genetics , Retinoid X Receptors/genetics , Thyroid Hormones/pharmacology , Acetates/chemical synthesis , Animals , Binding Sites , Brain/drug effects , Brain/immunology , Brain/pathology , 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/immunology , Mice , Mice, Inbred C57BL , Microglia/immunology , Microglia/pathology , Models, Molecular , Phenols/chemical synthesis , 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/immunology , Response Elements , Retinoid X Receptors/chemistry , Retinoid X Receptors/metabolism , Signal TransductionABSTRACT
A characteristic feature of COVID-19 disease is lymphopenia. Lymphopenia occurs early in the clinical course and is a predictor of disease severity and outcomes. The mechanism of lymphopenia in COVID-19 is uncertain. It has been variously attributed to the release of inflammatory cytokines including IL-6 and TNF-α; direct infection of the lymphocytes by the virus; and rapid sequestration of lymphocytes in the tissues. Additionally, we postulate that prostaglandin D2 (PGD2) is a key meditator of lymphopenia in COVID-19. First, SARS-CoV infection is known to stimulate the production of PGD2 in the airways, which inhibits the host dendritic cell response via the DP1 receptor signaling. Second, PGD2 is known to upregulate monocytic myeloid-derived suppressor cells (MDSC) via the DP2 receptor signaling in group 2 innate lymphoid cells (ILC2). We propose targeting PGD2/DP2 signaling using a receptor antagonist such as ramatroban as an immunotherapy for immune dysfunction and lymphopenia in COVID-19 disease.