RESUMEN
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.
Asunto(s)
Acetatos/farmacología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Glicoproteínas de Membrana/genética , Microglía/efectos de los fármacos , Fenoles/farmacología , Receptores Inmunológicos/genética , Receptores X Retinoide/genética , Hormonas Tiroideas/farmacología , Acetatos/síntesis química , Animales , Sitios de Unión , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/patología , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Regulación de la Expresión Génica , Humanos , Inmunidad Innata , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/patología , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Microglía/inmunología , Microglía/patología , Modelos Moleculares , Fenoles/síntesis química , Fenoxiacetatos/farmacología , Regiones Promotoras Genéticas , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/genética , ARN Mensajero/inmunología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/inmunología , Elementos de Respuesta , Receptores X Retinoide/química , Receptores X Retinoide/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Uptake of coronaviruses by target cells involves binding of the virus by cell ectoenzymes. For the etiologic agent of COVID-19 (SARS-CoV-2), a receptor has been identified as angiotensin-converting enzyme-2 (ACE2). Recently it has been suggested that plasma membrane integrins may be involved in the internalization and replication of clinically important coronaviruses. For example, integrin αvß3 is involved in the cell uptake of a model porcine enteric α-coronavirus that causes human epidemics. ACE2 modulates the intracellular signaling generated by integrins. OBJECTIVE: We propose that the cellular internalization of αvß3 applies to uptake of coronaviruses bound to the integrin, and we evaluate the possibility that clinical host T4 may contribute to target cell uptake of coronavirus and to the consequence of cell uptake of the virus. DISCUSSION AND CONCLUSIONS: The viral binding domain of the integrin is near the Arg-Gly-Asp (RGD) peptide-binding site and RGD molecules can affect virus binding. In this same locale on integrin αvß3 is the receptor for thyroid hormone analogues, particularly, L-thyroxine (T4). By binding to the integrin, T4 has been shown to modulate the affinity of the integrin for other proteins, to control internalization of αvß3 and to regulate the expression of a panel of cytokine genes, some of which are components of the 'cytokine storm' of viral infections. If T4 does influence coronavirus uptake by target cells, other thyroid hormone analogues, such as deaminated T4 and deaminated 3,5,3'-triiodo-L-thyronine (T3), are candidate agents to block the virus-relevant actions of T4 at integrin αvß3 and possibly restrict virus uptake.
Asunto(s)
Infecciones por Coronavirus/virología , Integrina alfaVbeta3/metabolismo , Virus de la Diarrea Epidémica Porcina/metabolismo , Receptores Virales/efectos de los fármacos , Hormonas Tiroideas/farmacología , Enzima Convertidora de Angiotensina 2 , Animales , Betacoronavirus/metabolismo , Sitios de Unión , COVID-19 , Citocinas/fisiología , Células Epiteliales/virología , Humanos , Oligopéptidos/metabolismo , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/virología , Receptores Virales/química , Receptores Virales/metabolismo , SARS-CoV-2 , Porcinos , Hormonas Tiroideas/fisiología , Tiroxina/fisiología , Internalización del VirusRESUMEN
Patients with COVID-19 are sometimes already being treated for one or more other chronic conditions, especially if they are elderly. Introducing a treatment against COVID-19, either on an outpatient basis or during hospitalization for more severe cases, raises the question of potential drug-drug interactions. Here, we analyzed the potential or proven risk of the co-administration of drugs used for the most common chronic diseases and those currently offered as treatment or undergoing therapeutic trials for COVID-19. Practical recommendations are offered, where possible.