Defects in Macrophage Specific Homeostatic Pathways in the Inflammatory Bowel Diseases Public Deposited

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  • March 22, 2019
Creator
  • Sheikh, Shehzad Zafar
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Intestinal macrophages are specialized to carry out their functions in the local antigen- and microbiota-rich environment. They are refractory to the induction of proinflammatory cytokines, yet still display potent phagocytic and bactericidal activity. These adaptations allow the intestinal macrophage to eradicate microbes that breach the intestinal epithelial barrier while maintaining local tissue homeostasis. The inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, results from an inappropriately directed inflammatory response to the enteric microbiota in a genetically susceptible host. In contrast to the characteristic anti-inflammatory phenotypic and functional profile of normal intestinal macrophages, these macrophages react to luminal microbes and become potent producers of proinflammatory cytokines such as IL-12 family members. IL-12 and 23 are heterodimeric cytokines produced by macrophages and dendritic cells that are important bridges between innate and adaptive immunity. Although the molecular events that lead to the expression of IL-12 and Il-23 in macrophages through TLR signaling have been well defined, anti-inflammatory pathways that lead to inhibition of these cytokines in macrophages have not been fully elucidated. We identify two important homeostatic pathways; IFN-γ and HO-1 that regulate enteric microbiota-induced production of IL-12 and 23 by macrophages. IFN-γ inhibits TLR induced IL-23 expression in macrophages, and these events prevent the initiation and progression of spontaneous IL-23-driven experimental colitis in IL-10 deficient (IL-10-/-) mice. Moreover, we demonstrate that enteric microbiota-induced heme-oxygenase 1 (HO- 1) is critical in the prevention of experimental colitis, through inhibition of IL-12 family members and augmentation of macrophage microbicidal pathways. In our first study we demonstrate that IFN-γ has anti-inflammatory properties in murine models of Th1/Th17 mediated experimental colitis through attenuation of TLRmediated IL-23 expression in macrophages. In the second series of experiments, using germ-free WT and colitis-prone IL-10-/- mice we show that intestinal HO-1 expression induced by the enteric microbiota is an important homeostatic pathway. We also identify signaling pathways (MyDD88, MAPK and Pi3K) essential for HO-1 induction in macrophages. Finally, in our third study, protective effects of the HO-1 pathway were determined in Th2-mediated chronic colonic inflammation in T cell receptor- alpha (TCRα) deficient (-/-) mice. TCRα-/- mice exposed to carbon monoxide (CO) or treated with a pharmacologic HO-1 inducer demonstrated significant amelioration of active colitis. We demonstrate that HO-1 regulates mucosal innate immune responses in the TCRα-/- mouse through IL-10 induction in colonic macrophages.
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  • In Copyright
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Microbiology and Immunology.
Advisor
  • Plevy, Scott E.
Degree granting institution
  • University of North Carolina at Chapel Hill
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