PTPN21/Pez Is a Novel and Evolutionarily Conserved Key Regulator of Inflammation In Vivo

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 (H(2)O(2)).(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, 4, 5 Similar H(2)O(2)-activated signaling pathways are also critical for leukocyte recruitment following wounding in larval zebrafish,6, 7, 8, 9 where H(2)O(2) 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 H(2)O(2) 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.