title: TLR4, TLR7/8 agonist-induced miR-146a promotes macrophage tolerance to MyD88-dependent TLR agonists.
abstract: TLRs facilitate the recognition of pathogens by immune cells and the initiation of the immune response, leading to the production of proinflammatory cytokines and chemokines. Production of proinflammatory mediators by innate immune cells, such as macrophages, is tightly regulated to facilitate pathogen clearance while limiting an adverse impact on host tissue. Exposure of innate immune cells to TLR ligands induces a state of temporary refractoriness to a subsequent exposure of a TLR ligand, a phenomenon referred to as "tolerance." This study sought to evaluate the mechanistic regulation of TLR4 and TLR7/8 ligand-induced tolerance to other TLRs by microRNA-146a. With the use of THP-1 macrophages, as well as human classic and alternative macrophages, we demonstrate that priming with a TLR4 agonist (LPS) or a TLR7/8 agonist (R848) induces homologous and heterologous tolerance to various TLR ligands in macrophages, leading to the impaired production of cytokines and chemokines. We also demonstrate that overexpression of microRNA-146a is sufficient to mimic LPS or R848-induced hyporesponsiveness. Conversely, inhibition of microRNA-146a activity leads to LPS- or R848-induced TLR hyper-responsiveness in TLR signaling tolerance. Furthermore, we demonstrate that microRNA-146a dampens cytokine production following a primary stimulus with MyD88-dependent but not MyD88-independent TLR pathways. Collectively, these data provide comprehensive evidence of the central role of microRNA-146a in TLR signaling tolerance to plasma membrane, as well as endosomal TLR ligands in human macrophages.
authors.affiliation: Immunology, Oncology, and Immunomodulatory Receptors Discovery Research, Merck Research Laboratories, Boston, Massachusetts, USA.
authors.forename: M Abu
authors.initials: MA
authors.lastname: Nahid
authors.affiliation: Immunology, Oncology, and Immunomodulatory Receptors Discovery Research, Merck Research Laboratories, Boston, Massachusetts, USA.
authors.forename: Lia M
authors.initials: LM
authors.lastname: Benso
authors.affiliation: Immunology, Oncology, and Immunomodulatory Receptors Discovery Research, Merck Research Laboratories, Boston, Massachusetts, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Shin
authors.affiliation: Immunology, Oncology, and Immunomodulatory Receptors Discovery Research, Merck Research Laboratories, Boston, Massachusetts, USA.
authors.forename: Huseyin
authors.initials: H
authors.lastname: Mehmet
authors.affiliation: Immunology, Oncology, and Immunomodulatory Receptors Discovery Research, Merck Research Laboratories, Boston, Massachusetts, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hicks
authors.affiliation: Immunology, Oncology, and Immunomodulatory Receptors Discovery Research, Merck Research Laboratories, Boston, Massachusetts, USA ravisankar.ramadas@merck.com.
authors.forename: Ravisankar A
authors.initials: RA
authors.lastname: Ramadas
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007108:Immune Tolerance / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000819:agonists*; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D051200:Toll-Like Receptor 8 / Q000819:agonists*
chemical_list: D016207:Cytokines; D007093:Imidazoles; D008070:Lipopolysaccharides; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D053594:Myeloid Differentiation Factor 88; C495345:TLR4 protein, human; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; C402365:resiquimod
keywords: microRNA; tolerance