PTPN21/Pez is a novel and evolutionarily conserved key regulator of inflammation in vivo

Jennie S. Campbell, Andrew J. Davidson, Henry Todd, Frederico S. L. M. Rodrigues, Abigail M. Elliot, Jason J. Early, David A. Lyons, Yi Feng, Will Wood

Research output: Contribution to journalArticlepeer-review

Abstract

Drosophila provides a powerful model in which to study inflammation in vivo and previous studies have revealed many of the key signalling events critical for recruitment of immune cells to tissue damage. In the fly, wounding stimulates the rapid production of hydrogen peroxide (H2O2) [1,2]. This then acts as an activation signal by triggering a signalling pathway within responding macrophages by directly activating the Src family kinase (SFK) Src42A [3] which, in turn, phosphorylates the damage receptor Draper. Activated Draper then guides macrophages to the wound, through the detection of an, as yet, unidentified chemoattractant [3,4,5]. Similar H2O2-activated signalling pathways are also critical for leukocyte recruitment following wounding in larval zebrafish [6,7,8,9] where H2O2 activates the SFK Lyn to drive neutrophil chemotaxis. In this study we combine proteomics, live imaging and genetics in the fly to identify a novel regulator of inflammation in vivo; the PTP type phosphatase Pez. Pez is expressed in macrophages and is critical for their efficient migration to wounds. Pez functions within activated macrophages downstream of damage-induced H2O2 and operates, via its FERM domain, together with Src42A and Draper to ensure effective inflammatory cell recruitment to wounds. We show that this key role is conserved in vertebrates, since ‘Crispant’ zebrafish larvae of the Draper orthologue (MEGF10) or the Pez orthologue (PTPN21) exhibit a failure in leukocyte recruitment to wounds. This study demonstrates evolutionary conservation of inflammatory signalling and identifies MEGF10 and PTPN21 as potential therapeutic targets for the treatment of inflammatory disorders.

Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalCurrent Biology
Volume31
Early online date8 Dec 2020
DOIs
Publication statusE-pub ahead of print - 8 Dec 2020

Keywords

  • Drosophila
  • zebrafish
  • inflammation
  • migration
  • neutrophil
  • macrophage
  • Draper
  • Pez
  • PTPN21
  • Megf10

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