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.

Gender-specific differential expression of exosomal miRNA in synovial fluid of patients with osteoarthritis

“…These two miRNAs are significantly down-regulated in female EV miRNAs. Published literature also confirms some of these target genes at mRNA and functional levels (using luciferase assay) 39, 63–65 .…”

Paeonol ameliorates imiquimod-induced psoriasis-like skin lesions in BALB/c mice by inhibiting the maturation and activation of dendritic cells

“…TLRs play a central role in the recognition and response to invading pathogens by immune cells, leading to the production of pro-inflammatory cytokines and chemokines (25). The TLR7/8, signaling pathway, which includes recruitment of MyD88, could be an important target for treating psoriasis.…”

miRNA regulation of innate immunity

“…Functionally, overexpression of miR‐146a was adequate to mimic LPS or R848‐induced hypo‐responsiveness . Contrarily, inhibition of miR‐146a activity leads to LPS‐ or R848‐induced TLR hyper‐responsiveness in TLR signaling tolerance through modulation of MyD88 in human macrophages …”

“…Nahid et al. showed that TLR4 agonist (LPS) and TLR7/8 ligand (R848) induce homologous and heterologous tolerance in monocyte/macrophages, which leads to aberrant production of chemokines and cytokines . Functionally, overexpression of miR‐146a was adequate to mimic LPS or R848‐induced hypo‐responsiveness .…”

“…showed that TLR4 agonist (LPS) and TLR7/8 ligand (R848) induce homologous and heterologous tolerance in monocyte/macrophages, which leads to aberrant production of chemokines and cytokines . Functionally, overexpression of miR‐146a was adequate to mimic LPS or R848‐induced hypo‐responsiveness . Contrarily, inhibition of miR‐146a activity leads to LPS‐ or R848‐induced TLR hyper‐responsiveness in TLR signaling tolerance through modulation of MyD88 in human macrophages …”