TLR4, TLR7/8 agonist-induced miR-146a promotes macrophage tolerance to MyD88-dependent TLR agonists

Journal of Leukocyte Biology
Md A NahidRavisankar A Ramadas

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. Furthe...Continue Reading

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Citations

Apr 16, 2018·Journal of Leukocyte Biology·Fatemeh Momen-Heravi, Shashi Bala
Oct 31, 2019·Cellular & Molecular Immunology·Siyuan ChenXiawei Wei
Sep 21, 2017·Frontiers in Immunology·Carlene PetesKatrina Gee
Oct 16, 2019·Journal of Cellular Physiology·Navid ShomaliSiamak Sandoghchian Shotorbani
Jul 29, 2019·Journal of Neuroinflammation·Nicholas J WaskoRobert B Clark
Dec 20, 2018·Frontiers in Immunology·Maryam G RohaniWilliam C Parks
Dec 23, 2020·Thrombosis and Haemostasis·Ana B ArroyoRocío González-Conejero
May 4, 2021·Seminars in Cell & Developmental Biology·Raza Ali NaqviAfsar R Naqvi
Jun 5, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Soudeh Ghafouri-FardMajid Mokhtari

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