TY - JOUR
T1 - Sequence-specific extracellular microRNAs activate TLR7 and induce cytokine secretion and leukocyte migration
AU - Wu, Niming
AU - Morsey, Brenda M.
AU - Emanuel, Katy M.
AU - Fox, Howard S.
N1 - Funding Information:
This work was supported by the National Institutes of Health [R01 DA040397, R21 MH106422, and P30 MH062261].
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
KW - Central nervous system disease
KW - Microglia
KW - TLRs
KW - TNF-α
KW - microRNA
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U2 - 10.1007/s11010-021-04220-3
DO - 10.1007/s11010-021-04220-3
M3 - Article
C2 - 34313894
AN - SCOPUS:85111375069
SN - 0300-8177
VL - 476
SP - 4139
EP - 4151
JO - Molecular and cellular biochemistry
JF - Molecular and cellular biochemistry
IS - 11
ER -