PUBLICATION

Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages in zebrafish spinal cord regeneration

Authors
Tsarouchas, T.M., Wehner, D., Cavone, L., Munir, T., Keatinge, M., Lambertus, M., Underhill, A., Barrett, T., Kassapis, E., Ogryzko, N., Feng, Y., van Ham, T.J., Becker, T., Becker, C.G.
ID
ZDB-PUB-181109-2
Date
2018
Source
Nature communications   9: 4670 (Journal)
Registered Authors
Becker, Catherina G., Becker, Thomas, Feng, Yi, Keatinge, Marcus, Ogryzko, Nikolay, Tsarouchas, Themistoklis, van Ham, Tjakko, Wehner, Daniel
Keywords
none
MeSH Terms
  • Spinal Cord/metabolism*
  • Spinal Cord/pathology
  • Zebrafish/immunology
  • Zebrafish/metabolism*
  • Nerve Regeneration*
  • Mutation/genetics
  • Animals
  • Macrophages/metabolism*
  • Collagen Type XII/metabolism
  • Tumor Necrosis Factor-alpha/metabolism*
  • Interleukin-1beta/metabolism*
  • Microglia/metabolism
  • Microglia/pathology
  • Axons/metabolism
  • Inflammation Mediators/metabolism*
  • Neutrophils/metabolism
(all 16)
PubMed
30405119 Full text @ Nat. Commun.
Abstract
Spinal cord injury leads to a massive response of innate immune cells in non-regenerating mammals, but also in successfully regenerating zebrafish. However, the role of the immune response in successful regeneration is poorly defined. Here we show that inhibiting inflammation reduces and promoting it accelerates axonal regeneration in spinal-lesioned zebrafish larvae. Mutant analyses show that peripheral macrophages, but not neutrophils or microglia, are necessary for repair. Macrophage-less irf8 mutants show prolonged inflammation with elevated levels of Tnf-α and Il-1β. Inhibiting Tnf-α does not rescue axonal growth in irf8 mutants, but impairs it in wildtype animals, indicating a pro-regenerative role of Tnf-α. In contrast, decreasing Il-1β levels or number of Il-1β+ neutrophils rescue functional regeneration in irf8 mutants. However, during early regeneration, interference with Il-1β function impairs regeneration in irf8 and wildtype animals. Hence, inflammation is dynamically controlled by macrophages to promote functional spinal cord regeneration in zebrafish.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
gl22TgTransgenic Insertion
    j4e1
      Point Mutation
      kyu2TgTransgenic Insertion
        ncv24TgTransgenic Insertion
          re01
            Small Deletion
            sh445TgTransgenic Insertion
              st95
                Small Deletion
                ue101TgTransgenic Insertion
                  ump5TgTransgenic Insertion
                    uwm1TgTransgenic Insertion
                      1 - 10 of 12
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                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      Target Reagent Reagent Type
                      csf3rMO1-csf3rMRPHLNO
                      il1bCRISPR4-il1bCRISPR
                      il1bMO1-il1bMRPHLNO
                      spi1bMO1-spi1bMRPHLNO
                      tnfaCRISPR4-tnfaCRISPR
                      1 - 5 of 5
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                      Fish
                      Antibodies
                      Orthology
                      No data available
                      Engineered Foreign Genes
                      Marker Marker Type Name
                      d2EGFPEFGd2EGFP
                      DsRedEFGDsRed
                      EGFPEFGEGFP
                      GAL4EFGGAL4
                      GAL4FFEFGGAL4FF
                      GFPEFGGFP
                      1 - 6 of 6
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                      Mapping