Cell Migration

Sensing H2O2 with Lyn

Sci. Signal.  06 Dec 2011:
Vol. 4, Issue 202, pp. ec341
DOI: 10.1126/scisignal.4202ec341

Tissue injury causes the production of reactive oxygen species, specifically hydrogen peroxide (H2O2) produced by NADPH oxidase, which is activated at the site of injury. This H2O2 signal triggers the migration of neutrophils to the site of injury. Yoo et al. provide evidence, using the model organism zebrafish, that H2O2 causes the oxidation of a specific cysteine in the intracellular Src family kinase (SFK) Lyn, which activates the kinase resulting in chemotaxis. Neutrophil recruitment to sites of tail injury in zebrafish larvae was compromised if SFK activity was inhibited or if dual oxidase, which produces H2O2 at the site of injury, was knocked down. Furthermore, neutrophils were recruited in response to H2O2 exogenously applied to the embryos and human neutrophils chemotaxed toward H2O2 in vitro, and these responses were blocked in the presence of SFK inhibitors. Knockdown of Lyn in the zebrafish embryos impaired neutrophil migration to sites of injury and inhibited wound-induced SFK autophosphorylation, which is required for catalytic activity. Mutational analysis of Lyn expressed in human embryonic kidney (HEK) 293 cells and in vitro kinase assays with the mutants showed that Cys466 was necessary for H2O2 to activate Lyn activity. The importance of Cys466 for neutrophil wound responses was confirmed by rescue experiments in zebrafish in which endogenous Lyn was knocked down. Thus, the authors concluded that oxidation of Cys466 activated Lyn, enabling Lyn to serve as the H2O2 sensor for promoting neutrophil migration to sites of injury.

S. K. Yoo, T. W. Starnes, Q. Deng, A. Huttenlocher, Lyn is a redox sensor that mediates leukocyte wound attraction in vivo. Nature 480, 109–112 (2011). [PubMed]