Drosophila provides a powerful model in which to study
inflammation in vivo, and previous studies have revealed many of the key signaling 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 signaling 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.3-5 Similar H2O2-activated signaling pathways are also critical for leukocyte recruitment following wounding in larval zebrafish,6-9 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 band 4.1
ezrin,
radixin, and
moesin (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, because "crispant" zebrafish larvae of the Draper ortholog (MEGF10) or the Pez ortholog (PTPN21) exhibit a failure in leukocyte recruitment to
wounds. This study demonstrates evolutionary conservation of inflammatory signaling and identifies MEGF10 and PTPN21 as potential therapeutic targets for the treatment of inflammatory disorders.