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

Abstract

AbstractThe 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 withLeishmania 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 toL. donovaniinfection and may represent a novel approach to mitigate immunopathology.