Macrophage-derived developmental endothelial locus 1 (DEL-1) expression promotes an immunoprotective phenotype in experimental visceral leishmaniasis

The identification of tissue-derived homeostatic molecules regulating immune plasticity is essential for understanding the role of macrophages in immune responses to intra-phagosomal pathogens. Developmental endothelial locus-1 (DEL-1) is a functionally versatile homeostatic factor capable of inhibiting the onset of inflammation and promoting inflammation resolution, but its role in the response to intracellular infections has not been previously addressed. Leishmania , causative agents of the neglected tropical disease leishmaniasis, are intra-phagosomal parasites that establish a replicative niche within macrophages. Here, using a well-established murine model of visceral infection with Leishmania donovani , we establish DEL-1 as a novel regulator of immunity to this infection. Parasite burden was significantly higher in B6. Edil3 -/- (Del1-KO) compared to wild type B6 mice, as determined by whole body IVIS imaging, largely as a result of increased liver parasite load. However, lack of DEL-1 enhanced hepatomegaly and enhanced granulomatous inflammation. Conversely, parasite burden and the formation of large granulomas was reduced in mice overexpressing DEL-1 in macrophages but not in endothelial cells. Our findings reveal a hitherto unknown role of DEL-1 in the immune response to L. donovani infection and may represent a novel approach to mitigate immunopathology. ### Competing Interest Statement The authors have declared no competing interest.