TLR4, TLR7/8 agonist-induced miR-146a promotes macrophage tolerance to MyD88-dependent TLR agonists
| Autor: | Lia Benso, John H. Shin, Ravisankar A. Ramadas, Huseyin Mehmet, Alexandra Hicks, A. Nahid |
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| Rok vydání: | 2016 |
| Předmět: |
Lipopolysaccharides
0301 basic medicine Agonist Chemokine medicine.drug_class medicine.medical_treatment Immunology Proinflammatory cytokine 03 medical and health sciences Immune system Immune Tolerance medicine Humans Immunology and Allergy Cells Cultured Innate immune system biology Macrophages Imidazoles Cell Biology TLR7 Cell biology Toll-Like Receptor 4 MicroRNAs 030104 developmental biology Cytokine Gene Expression Regulation Toll-Like Receptor 7 Toll-Like Receptor 8 Myeloid Differentiation Factor 88 biology.protein TLR4 Cytokines |
| Zdroj: | Journal of Leukocyte Biology. 100:339-349 |
| ISSN: | 1938-3673 0741-5400 |
| DOI: | 10.1189/jlb.2a0515-197r |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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