Lipid peroxidation regulates long-range wound detection through 5-lipoxygenase in zebrafish.

Rapid wound detection by distant leukocytes is essential for antimicrobial defense and post-infection survival (1). The reactive oxygen species hydrogen peroxide and the polyunsaturated fatty acid arachidonic acid are among the earliest known mediators of this process (2-4). It is unknown whether or how these highly conserved cues collaborate to achieve wound detection over distances of several hundreds of microns within a few minutes. To investigate this, we locally applied arachidonic acid and skin permeable peroxide by micropipette perfusion to unwounded zebrafish tail fins. As in wounds, arachidonic acid rapidly attracted leukocytes through dual oxidase (Duox) and 5-lipoxygenase (Alox5a). Peroxide promoted chemotaxis to arachidonic acid without being chemotactic on its own. Intravital biosensor imaging showed that wound peroxide and arachidonic acid converged on half-millimeter long lipid peroxidation gradients that promoted leukocyte attraction. Our data suggest that lipid peroxidation functions as spatial redox relay that enables long-range detection of early wound cues by immune cells, outlining a beneficial role for this otherwise toxic process.