Fly wounds and tumors restrict macrophages via a matrix degradation-moderating protease inhibitor

Breaches of epithelial homeostasis trigger an inflammatory response. Not only initiation but 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 thioester-containing protein Tep3 from Drosophila limits innate immune cell attachment to damaged and transformed epithelia. Tep3 is produced in wounds and tumors alongside the matrix metalloprotease MMP1. Tep3 inhibits MMP1 proteolytic activity, reducing production of a BM DAMP that is necessary for macrophage association. A Drosophila tumor upregulates Tep3 to limit an MMP1- and macrophage-dependent anti-tumor immune response, thus accelerating progression and host death. Hence, fly tumors can exploit a physiological anti-inflammatory axis to pathologically limit their immune restriction.