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

Tissue wounding induces the rapid recruitment of leukocytes(1). Wounds and tumors, a type of “unhealed wound”(2), generate hydrogen peroxide (H(2)O(2)) through a NADPH oxidase (NOX) and the extracellular H(2)O(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(2)O(2) following tissue injury and inhibition of Lyn attenuates neutrophil wound recruitment. Inhibition of SFKs also disrupted H(2)O(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.