Macrophage restriction in Drosophila wounds and tumors via a matrix degradation-moderating protease inhibitor.

Breaches of epithelial homeostasis trigger an inflammatory response. Not only initiation but also negative regulation of the response is critical, as autoinflammation can cause tissue damage and chronic disease. Epithelial breaches can be signaled by damage-associated molecular patterns (DAMPs), including basement membrane (BM) degradation, that attract inflammatory cells. Here, we show that the conserved glycosylphosphatidylinositol-linked thioester-containing protein Tep3 from Drosophila, the ortholog of human CD109, limits innate immune cell attachment to damaged and transformed epithelia. Tep3 is induced in wounds alongside the matrix metalloprotease 1 (MMP1). Tep3 inhibits MMP1 proteolytic activity, reducing production of a BM DAMP that triggers macrophage association. A Drosophila tumor up-regulates Tep3 to limit an MMP1- and macrophage-dependent antitumor immune response, thus accelerating progression and host death. Hence, fly tumors can exploit a physiological anti-inflammatory axis to pathologically limit their immune restriction.