The Role of α(1,3)-Fucosylated Glycans in Homeostatic Immunity, Granulopoiesis, and Mucosal Injury. Public Deposited

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  • March 19, 2019
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  • Mackey, Lantz
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
Abstract
  • The mechanisms that control granulopoiesis are poorly understood. Mice deficient in &alpha;(1,3)-fucosyltransferases (FUT) 4 and 7 (Fut<super>-/-</super>) 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<super>-/-</super> mice and how they alter the pathogenesis of colitis. The results show that Fut<super>-/-</super> 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<super>-/-</super> 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<super>-/-</super> 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<super>-/-</super>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<super>-/-</super>/Fut<super>-/-</super> deficient mice. Absence of Tcells and Bcells did not alter disease severity in Fut<super>-/-</super> 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.
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  • In Copyright
Advisor
  • Fedoriw, Yuri
  • Funkhouser, William
  • Wan, Yisong
  • Doerschuk, Claire
  • Homeister, Jonathon
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2014
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  • Chapel Hill, NC
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