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

Rapid wound detection by distant leukocytes is essential for antimicrobial defence 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 micrometres 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-millimetre-long lipid peroxidation gradients that promoted leukocyte attraction. Our data suggest that lipid peroxidation functions as a spatial redox relay that enables long-range detection of early wound cues by immune cells, outlining a beneficial role for this otherwise toxic process. Two complementary studies from the laboratories of Riegman et al. and Katikaneni et al., respectively, identify a key role for controlled wave-like propagation of lipid peroxide signalling during wound detection in vivo, and in ferroptotic cell death.