PUBLICATION

Deficiency in Hematopoietic Phosphatase Ptpn6/Shp1 Hyperactivates the Innate Immune System and Impairs Control of Bacterial Infections in Zebrafish Embryos

Authors
Kanwal, Z., Zakrzewska, A., den Hertog, J., Spaink, H.P., Schaaf, M.J., and Meijer, A.H.
ID
ZDB-PUB-130131-13
Date
2013
Source
Journal of immunology (Baltimore, Md. : 1950)   190(4): 1631-1645 (Journal)
Registered Authors
den Hertog, Jeroen, Kanwal, Zakia, Meijer, Annemarie H., Schaaf, Marcel J. M., Spaink, Herman P., Zakrzewska, Ania
Keywords
none
Datasets
GEO:GSE34930
MeSH Terms
  • Immunophenotyping
  • Animals
  • Salmonella Infections/enzymology*
  • Salmonella Infections/genetics
  • Salmonella Infections/immunology*
  • Models, Animal
  • Zebrafish Proteins/deficiency*
  • Zebrafish Proteins/genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6/deficiency*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6/genetics*
  • Embryo, Nonmammalian
  • Zebrafish*
  • Immunity, Innate/genetics*
(all 13)
PubMed
23335748 Full text @ J. Immunol.
Abstract

Deficiency in Src homology region 2 domain-containing phosphatase 1/protein tyrosine phosphatase nonreceptor type 6 (SHP1/PTPN6) is linked with chronic inflammatory diseases and hematological malignancies in humans. In this study, we exploited the embryonic and larval stages of zebrafish (Danio rerio) as an animal model to study ptpn6 function in the sole context of innate immunity. We show that ptpn6 knockdown induces a spontaneous inflammation-associated phenotype at the late larval stage. Surprisingly, glucocorticoid treatment did not suppress inflammation under ptpn6 knockdown conditions but further enhanced leukocyte infiltration and proinflammatory gene expression. Experiments in a germ-free environment showed that the late larval phenotype was microbe independent. When ptpn6 knockdown embryos were challenged with Salmonella typhimurium or Mycobacterium marinum at earlier stages of development, the innate immune system was hyperactivated to a contraproductive level that impaired the control of these pathogenic bacteria. Transcriptome analysis demonstrated that Kyoto Encyclopedia of Genes and Genomes pathways related to pathogen recognition and cytokine signaling were significantly enriched under these conditions, suggesting that ptpn6 functions as a negative regulator that imposes a tight control over the level of innate immune response activation during infection. In contrast to the hyperinduction of proinflammatory cytokine genes under ptpn6 knockdown conditions, anti-inflammatory il10 expression was not hyperinduced. These results support that ptpn6 has a crucial regulatory function in preventing host-detrimental effects of inflammation and is essential for a successful defense mechanism against invading microbes.

Genes / Markers
Figures
No images available
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
i114TgTransgenic Insertion
    y1TgTransgenic Insertion
      zdf1
        Point Mutation
        zf44TgTransgenic Insertion
          zf113TgTransgenic Insertion
            1 - 5 of 5
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            Human Disease / Model
            No data available
            Sequence Targeting Reagents
            Target Reagent Reagent Type
            ptpn6MO1-ptpn6MRPHLNO
            ptpn6MO2-ptpn6MRPHLNO
            ptpn6MO3-ptpn6MRPHLNO
            1 - 3 of 3
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            Fish
            Antibodies
            Name Type Antigen Genes Isotypes Host Organism
            Ab1-lcp1polyclonalRabbit
            1 - 1 of 1
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            Orthology
            No data available
            Engineered Foreign Genes
            Marker Marker Type Name
            EGFPEFGEGFP
            GFPEFGGFP
            RFPEFGRFP
            1 - 3 of 3
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            Mapping