Targeting of microRNA-142-3p in dendritic cells regulates endotoxin-induced mortality

Yaping Sun, Sooryanarayana Varambally, Christopher A. Maher, Qi Cao, Peter Chockley, Tomomi Toubai, Chelsea Malter, Evelyn Nieves, Isao Tawara, Yongqing Wang, Peter A. Ward, Arul Chinnaiyan, Pavan Reddy*

*Corresponding author for this work

Research output: Contribution to journalArticle

104 Scopus citations

Abstract

While miRNAs are increasingly linked to various immune responses, whether they can be targeted for regulating in vivo inflammatory processes such as endotoxininduced Gram-negative sepsis is not known. Production of cytokines by the dendritic cells (DCs) plays a critical role in response to endotoxin, lipopolysaccharide (LPS). We profiled the miRNA and mRNA of CD11c+ DCs in an unbiased manner and found that at baseline, miR-142-3p was among the most highly expressed endogenous miRs while IL-6 was among the most highly expressed mRNA after LPS stimulation. Multiple computational algorithms predicted the IL-6 3′ untranslated region (UTR) to be a target of miR-142-3p. Studies using luciferase reporters carrying wild-type (WT) and mutant IL-6 3′UTR confirmed IL-6 as a target for miR-142-3p. In vitro knockdown and overexpression studies demonstrated a critical and specific role for miR142-3p in regulating IL-6 production by the DCs after LPS stimulation. Importantly, treatment of only WT but not the IL-6-deficient (IL-6-/-) mice with locked nucleic acid (LNA)-modified phosphorothioate oligonucleotide complementary to miR 142-3p reduced endotoxin-induced mortality. These results demonstrate a critical role for miR-142-3p in regulating DC responses to LPS and provide proof of concept for targeting miRs as a novel strategy for treatment of endotoxin-induced mortality.

Original languageEnglish (US)
Pages (from-to)6172-6183
Number of pages12
JournalBlood
Volume117
Issue number23
DOIs
StatePublished - Jun 9 2011

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Sun, Y., Varambally, S., Maher, C. A., Cao, Q., Chockley, P., Toubai, T., Malter, C., Nieves, E., Tawara, I., Wang, Y., Ward, P. A., Chinnaiyan, A., & Reddy, P. (2011). Targeting of microRNA-142-3p in dendritic cells regulates endotoxin-induced mortality. Blood, 117(23), 6172-6183. https://doi.org/10.1182/blood-2010-12-325647