Lyn is a redox sensor that mediates leukocyte wound attraction in vivo

Summary

Tissue wounding induces the rapid recruitment of leukocytes ¹ . Wounds and tumors, a type of “unhealed wound” ² , generate hydrogen peroxide (H ₂O ₂) through a NADPH oxidase (NOX) and the extracellular H ₂O ₂ mediates recruitment of leukocytes, particularly first responders of innate immunity, neutrophils, to injured tissue ^{3– 6} . However, it is not known what sensor neutrophils use to detect the redox state at wounds. Here we identify the Src family kinase (SFK) Lyn as a redox sensor that mediates initial neutrophil recruitment to wounds in zebrafish larvae. Lyn activation in neutrophils is dependent on wound-derived H ₂O ₂ following tissue injury and inhibition of Lyn attenuates neutrophil wound recruitment. Inhibition of SFKs also disrupted H ₂O ₂-mediated chemotaxis of primary human neutrophils. In vitro analysis identified a single cysteine residue, C466, as being responsible for direct oxidation-mediated activation of Lyn. Furthermore, transgenic tissue-specific reconstitution with wild-type Lyn and a cysteine mutant revealed that Lyn C466 is important for the neutrophil wound response and downstream signaling in vivo. This is the first identification, to our knowledge, of a physiological redox sensor that mediates leukocyte wound attraction in multicellular organisms.