Editors' ChoiceImmunology

From tissue damage to adaptive immunity

See allHide authors and affiliations

Science Signaling  23 Jun 2015:
Vol. 8, Issue 382, pp. ec166
DOI: 10.1126/scisignal.aac8172

Wounding induces local production of hydrogen peroxide (H2O2), which attracts leukocytes to the site of injury. In vertebrates, H2O2 induced by tissue damage oxidizes a particular cysteine residue in the Src family kinase (SFK) Lyn, which stimulates Lyn activity in neutrophils and promotes their migration into the wound. Src42A is the only SFK in Drosophila melanogaster in which this redox-sensitive cysteine residue is conserved. Src42A phosphorylates the intracellular ITAM (immunoreceptor tyrosine-based activation motif) of Draper-I, the Drosophila homolog of the apoptotic cell clearance receptor CED-1. ITAM-phosphorylated Draper-I recruits the Syk-related kinase Shark to propagate signaling. Evans et al. found that Src42A was not required for the normal proliferation, specification, or mobility of hemocytes, the phagocytic innate immune cells of the fly that are analogous to macrophages, but Src42A was required for their directed migration into laser-induced wounds in the embryonic epidermis. Knocking down draper or shark in hemocytes impaired their migration into wounds. Whereas expression of wild-type Draper-I rescued hemocyte migration to wounds in draper mutants, expression of a Draper-I mutant that was not phosphorylated by Src42A did not. This mechanism controlling the migration of fly immune cells to wound sites is similar to the vertebrate adaptive immune response in which Lyn-mediated phosphorylation of immunoreceptor ITAMs recruits the Syk family kinase ZAP-70. The authors propose that this vertebrate adaptive immune signaling pathway (Lyn-ITAM-ZAP-70) may have evolved from a damage-sensing system, represented by the Src42A-Draper-Shark axis that governs targeted migration of hemocytes in flies.

I. R. Evans, F. S. L. M. Rodrigues, E. L. Armitage, W. Wood, Draper/CED-1 mediates an ancient damage response to control inflammatory blood cell migration in vivo. Curr. Biol. 25, 1606–1612 (2015). [PubMed]