Article ; Online: Sequence-specific extracellular microRNAs activate TLR7 and induce cytokine secretion and leukocyte migration.
Molecular and cellular biochemistry
2021 Volume 476, Issue 11, Page(s) 4139–4151
Abstract: Toll-like receptors (TLRs) can contribute to central nervous system disease pathologies via recognition of microRNAs (miRNAs); however, it remains to be determined which miRNAs are able to activate this signaling. Here we report that numerous miRNAs ... ...
| Abstract | Toll-like receptors (TLRs) can contribute to central nervous system disease pathologies via recognition of microRNAs (miRNAs); however, it remains to be determined which miRNAs are able to activate this signaling. Here we report that numerous miRNAs induced the production of tumor necrosis factor alpha in multiple myeloid cell types, including microglia, and that this effect was abolished in cells deficient in TLR7. Examination of closely related miRNAs that differed in their ability to activate TLR7 resulted in the identification of a motif (UGCUUAU) in miR-20a-5p and specific nucleotides (all the uridines and surprisingly the cytosine as well) in a key area of miR-20a-5p and miR-148b-3p that were vital for the secretion of cytokines via TLR7 stimulation. A 10-nucleotide sequence including this motif was identified to be the shortest single-stranded RNA to signal via TLR7. An miRNA containing this motif induced the secretion of multiple proinflammatory molecules, which was dependent on the phosphoinositide 3-kinase, mitogen-activated protein kinase, and nuclear factor kappa-light-chain-enhancer of activated B cell signaling pathways. Wild-type mice administered miR-20a-5p, which contained this motif, demonstrated increased leukocyte migration. This effect was significantly ameliorated in TLR7-knockout mice, and mice administered miR-20b-5p, in which the motif was mutated, did not exhibit leukocyte migration. We provide a detailed analysis of miRNAs that activate endosomal TLR7 and identify key nucleotide features of a sequence motif recognized by TLR7. |
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| MeSH term(s) | Animals ; Base Sequence ; Cell Movement/physiology ; Cells, Cultured ; Cytokines/immunology ; Cytokines/metabolism ; Disease Models, Animal ; Leukocytes/immunology ; Leukocytes/metabolism ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/immunology ; Membrane Glycoproteins/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; MicroRNAs/genetics ; MicroRNAs/immunology ; MicroRNAs/metabolism ; Toll-Like Receptor 7/genetics ; Toll-Like Receptor 7/immunology ; Toll-Like Receptor 7/metabolism ; Tumor Necrosis Factor-alpha/metabolism |
| Chemical Substances | Cytokines ; Membrane Glycoproteins ; MicroRNAs ; Mirn20 microRNA, mouse ; Tlr7 protein, mouse ; Toll-Like Receptor 7 ; Tumor Necrosis Factor-alpha |
| Language | English |
| Publishing date | 2021-07-27 |
| Publishing country | Netherlands |
| Document type | Journal Article |
| ZDB-ID | 184833-1 |
| ISSN | 1573-4919 ; 0300-8177 |
| ISSN (online) | 1573-4919 |
| ISSN | 0300-8177 |
| DOI | 10.1007/s11010-021-04220-3 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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