PUBLICATION

MicroRNA-146 function in the innate immune transcriptome response of zebrafish embryos to Salmonella typhimurium infection

Authors
Ordas, A., Kanwal, Z., Lindenberg, V., Rougeot, J., Mink, M., Spaink, H.P., and Meijer, A.H.
ID
ZDB-PUB-131113-1
Date
2013
Source
BMC Genomics   14(1): 696 (Journal)
Registered Authors
Kanwal, Zakia, Meijer, Annemarie H., Rougeot, Julien, Spaink, Herman P.
Keywords
MicroRNA, miR-146, innate immunity, Salmonella typhimurium, mycobacterium marinum, MyD88, Traf6, apolipoproteins, zebrafish
Datasets
GEO:GSE45209, GEO:GSE45409, GEO:GSE45410
MeSH Terms
  • Animals
  • Apolipoproteins/genetics
  • Apolipoproteins/metabolism
  • Embryo, Nonmammalian/immunology*
  • Embryo, Nonmammalian/metabolism
  • Embryo, Nonmammalian/microbiology*
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Humans
  • Immunity, Innate/genetics*
  • Inflammation/genetics
  • Leukocytes/metabolism
  • MicroRNAs/genetics
  • MicroRNAs/metabolism*
  • Mycobacterium/physiology
  • Oligonucleotide Array Sequence Analysis
  • Salmonella Infections, Animal/genetics*
  • Salmonella Infections, Animal/immunology
  • Salmonella Infections, Animal/microbiology
  • Salmonella typhimurium/physiology
  • Signal Transduction/genetics
  • Transcriptome/genetics*
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zebrafish/immunology
  • Zebrafish/microbiology
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
24112639 Full text @ BMC Genomics
Abstract

Background

MicroRNAs (miRNAs) have recently been shown to play important roles in development of the immune system and in fine-tuning of immune responses. Human miR-146 family members are known as inflammation-inducible miRNAs involved in negative feedback regulation of Toll-like receptor (TLR) signalling. Dysregulation of the miR-146 family has often been linked to inflammatory diseases and malignancies. This study reports on miR-146a and miR-146b as infection-inducible miRNAs in zebrafish, which has emerged as a model species for human disease.

Results

Using a custom-designed microarray platform for miRNA expression we found that both members of the zebrafish miR-146 family, miR-146a and miR-146b, were commonly induced by infection of zebrafish embryos with Salmonella typhimurium and by infection of adult fish with Mycobacterium marinum. The induction of these miRNAs was confirmed by Taqman miRNA assays. Subsequently, we used zebrafish embryos, in which adaptive immunity is not yet active, as an in vivo system to investigate the role of miR-146 in the innate immune response to S. typhimurium infection. Knockdown of traf6 and use of myd88 mutants demonstrated that the induction of miR-146a and miR-146b by S. typhimurium infection was affected by disruption of the MyD88-Traf6 pathway that mediates transduction of TLR signals and cytokine responses. In turn, knockdown of miR-146 itself had no major effects on the expression of known targets of MyD88-Traf6 signalling. Instead, RNA sequencing analysis showed that miR-146 knockdown led to an increased induction of six members of the apolipoprotein gene family in S. typhimurium-infected embryos.

Conclusion

Based on microarray analysis and Taqman miRNA assays we conclude that members of the miR-146 family, which is highly conserved between fish and human, are induced by bacterial infection in zebrafish in a MyD88 and Traf6 dependent manner. The combined knockdown of miR-146a and miR-146b in zebrafish embryos infected with S. typhimurium had no major effect on the expression of pro-inflammatory genes and transcription factors known to be downstream of the MyD88-Traf6 pathway. In contrast, apolipoprotein-mediated lipid transport emerged as an infection-inducible pathway under miR-146 knockdown conditions, suggesting a possible function of miR-146 in regulating lipid metabolism during inflammation.

Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping