The role of alpha(1,3)-fucosylated glycans in homeostatic immunity, granulopoiesis and mucosal injury.

摘要

The mechanisms that control granulopoiesis are poorly understood. Mice deficient in alpha(1,3)-fucosyltransferases (FUT) 4 and 7 (Fut-/- ) lack selectin ligand activity and selectin-dependent leukocyte trafficking, and have a marked neutrophilia compared to WT mice. These studies utilize mouse models to examine the mechanisms that account for enhanced granulopoiesis in Fut-/- mice and how they alter the pathogenesis of colitis. The results show that Fut-/- mice have elevated circulating IL-17 and G-CSF concentrations, increased prevalence of IL-17-producing cells, and a marked neutrophilia compared to WT mice. Analysis of selectin-deficient mice showed that loss of all three selectins (E-,L-, and P-) induced the neutrophilia and enhanced IL-17 production, similar to Fut-/- mice. These results suggest that loss of Fut-dependent selectin-mediated leukocyte trafficking alters granulopoiesis by modulating a previously proposed IL-17-dependnent granulopoietic regulatory loop.;Experiments using bone marrow transplants, adoptive neutrophil transfer, and myeloid-specific alteration of FUT7 expression revealed that BM-derived myeloid cell trafficking is primarily responsible for regulating granulopoiesis. In vitro analysis of BM-derived and tissue resident phagocyte populations reveal no defect in phagocytosis or IL-23 production in Fut-/- mice. Together these results suggest Fut-dependent selectin-mediated myeloid cell trafficking, not tissue phagocyte function, regulates granulopoiesis.;DSS-induced murine colitis is largely dependent on the innate immune system and is exacerbated by elevated IL-17. Compared to WT, colitis in Fut -/-mice was more severe, determined by weight loss, occult bleeding, and histology. The role of Tcell-derived IL-17 in the development of colitis was examined using Rag1-/-/Fut-/- deficient mice. Absence of Tcells and Bcells did not alter disease severity in Fut -/- mice.;The results from these studies highlight the importance of Fut-dependent leukocyte trafficking of BM derived myeloid cells in regulating IL-17-dependent granulopoiesis and modulating disease severity in DSS-colitis. Taken together these studies demonstrate that leukocyte trafficking is required to maintain homeostatic immunity, and that disruption can lead to significant alterations in the inflammatory state.