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Title: Mononuclear phagocytes in intestinal homeostasis and inflammation
Author: Mathisen, Stephanie Jane
ISNI:       0000 0004 6060 6098
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Changes to the composition and function of the gut mononuclear phagocyte (MNP) compartment are associated with the development of intestinal inflammation. Much work has focused on the role of MNPs in gut-associated lymphoid tissue in maintaining homeostasis, however little is known regarding the roles of MNPs during colitis. We have investigated MNPs in the large intestinal lamina propria during the steady state and inflammation. One of our primary aims was to determine the contribution of MNP subsets to intestinal pathology. For our studies of inflammation, we focused mainly on the Helicobacter hepaticus infection + anti-IL-10R model, which induces inflammation of the colon and caecum (typhlocolitis). We defined the composition of the MNP compartment alongside intestinal pathology scores throughout Hh + anti-IL-10R typhlocolitis. Peak pathology, 2-3 weeks after induction of colitis, coincided with peak frequencies of CX3CR1int Ly6C+ MNPs. Having observed the accumulation of CX3CR1int CD64+ monocyte/macrophage MNPs in the inflamed lamina propria, we conducted comparative whole genome microarray analysis of these cells isolated from the large intestine three weeks after Hh + anti-IL-10R treatment. CX3CR1int CD64+ MNPs selectively expressed a variety of pro- and anti-inflammatory genes, including a number of genes which individually can both promote and negatively regulate inflammation. IL-23 is essential for Hh + anti-IL-10R-induced intestinal pathology. We investigated the role of MNPs as a source of IL-23 which drives Hh + anti-IL-10R colitis. Unexpectedly, our results indicate that normally hyporesponsive CX3CR1hi macrophages may act as the initial source of IL-23, which induces development of colitis. Recruitment of Ly6C+ MHCII+ MNPs to the lamina propria was IL-23-dependent, and these cells also expressed IL-23, which may establish a positive feedback loop of immune cell recruitment, activation and IL-23 production. Finally, we also examined how MNPs might be recruited to the colonic lamina propria during inflammation. Our studies support the conclusion that CCR6 is not required for accumulation of monocyte-derived populations in the inflamed intestine. We cannot rule out a role for CCR2, however preliminary data from the Hh + anti-IL-10R colitis model suggest a potential role for CCR1 or its close relation CCRL2. Such pathways could represent new therapeutic targets in inflammatory bowel disease.
Supervisor: Powrie, Fiona ; Taylor, Philip ; Udalova, Irina Sponsor: Biotechnology and Biological Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Mucosal Immunology ; Mononuclear Phagocytes ; Immunology ; Macrophages ; Monocytes ; Inflammatory Bowel Disease ; Colitis ; Interleukin-23 (IL-23) ; Intestinal Immunology ; Intestinal Inflammation