PUBLICATION

Uricase-Deficient Larval Zebrafish with Elevated Urate Levels Demonstrate Suppressed Acute Inflammatory Response to Monosodium Urate Crystals and Prolonged Crystal Persistence

Authors
Linnerz, T., Sung, Y.J., Rolland, L., Astin, J.W., Dalbeth, N., Hall, C.J.
ID
ZDB-PUB-221224-15
Date
2022
Source
Genes   13(12): (Journal)
Registered Authors
Astin, Jonathan, Hall, Chris, Linnerz, Tanja, Rolland, Leah, Sung, Yih Jian
Keywords
CRISPR/Cas9, MSU crystals, gout, hyperuricemia, inflammation, urate, uricase, zebrafish
MeSH Terms
  • Animals
  • Gout*/genetics
  • Humans
  • Inflammation
  • Urate Oxidase/genetics
  • Uric Acid*
  • Zebrafish/genetics
(all 7)
PubMed
36553446 Full text @ Genes (Basel)
Abstract
Gout is caused by elevated serum urate leading to the deposition of monosodium urate (MSU) crystals that can trigger episodes of acute inflammation. Humans are sensitive to developing gout because they lack a functional urate-metabolizing enzyme called uricase/urate oxidase (encoded by the UOX gene). A hallmark of long-standing disease is tophaceous gout, characterized by the formation of tissue-damaging granuloma-like structures ('tophi') composed of densely packed MSU crystals and immune cells. Little is known about how tophi form, largely due to the lack of suitable animal models in which the host response to MSU crystals can be studied in vivo long-term. We have previously described a larval zebrafish model of acute gouty inflammation where the host response to microinjected MSU crystals can be live imaged within an intact animal. Although useful for modeling acute inflammation, crystals are rapidly cleared following a robust innate immune response, precluding analysis at later stages. Here we describe a zebrafish uox null mutant that possesses elevated urate levels at larval stages. Uricase-deficient 'hyperuricemic' larvae exhibit a suppressed acute inflammatory response to MSU crystals and prolonged in vivo crystal persistence. Imaging of crystals at later stages reveals that they form granuloma-like structures dominated by macrophages. We believe that uox-/- larvae will provide a useful tool to explore the transition from acute gouty inflammation to tophus formation, one of the remaining mysteries of gout pathogenesis.
Genes / Markers
Figures
Figure Gallery (6 images)
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
c264TgTransgenic Insertion
    gl28TgTransgenic Insertion
      nz54TgTransgenic Insertion
        nz55TgTransgenic Insertion
          nz56
            Insertion
            nz117TgTransgenic Insertion
              1 - 6 of 6
              Show
              Human Disease / Model
              Sequence Targeting Reagents
              Target Reagent Reagent Type
              uoxCRISPR2-uoxCRISPR
              1 - 1 of 1
              Show
              Fish
              Antibodies
              No data available
              Orthology
              No data available
              Engineered Foreign Genes
              Marker Marker Type Name
              EGFPEFGEGFP
              KALTA4EFGKALTA4
              mCherryEFGmCherry
              NTREFGNTR
              1 - 4 of 4
              Show
              Mapping
              No data available