O'Shea, NR; (2016) An investigation of ADAM-like Decysin 1 in macrophage-mediated inflammation and Crohn's Disease. Doctoral thesis , UCL (University College London).

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Abstract

Crohn’s disease (CD) is now recognised as a defective host response to bacteria in genetically susceptible individuals. The role of innate immunity and impaired bacterial clearance are widely accepted. In this thesis the role of ADAM-like, Decysin-1 (ADAMDEC1) in macrophage-mediated inflammation and gut mucosal immunity is explored. Using transcriptomic analysis of monocyte derived macrophages (MDM) ADAMDEC1 was identified as grossly under expressed in a subset of patients with CD. ADAMDEC1 was found to be highly selective to the intestine, peripheral blood monocyte-derived and lamina propria macrophages. It was shown to be an inflammatory response gene, upregulated in response to bacterial antigens and inflammation. ADAMDEC1 was expressed in prenatal and germ free mice, demonstrating exposure to a bacterial antigen is not a prerequisite for expression. Adamdec1 knock out mice were used to investigate the role of ADAMDEC1 in vivo. Adamdec1-/- mice displayed an increased susceptibility to dextran sodium sulphate (DSS), Citrobacter rodentium and Salmonella typhimurium induced colitis. In Adamdec1-/- mice, bacterial translocation and systemic infection were increased in bacterial models of colitis. These results suggest that individuals with grossly attenuated expression of ADAMDEC1 may be at an increased risk of developing intestinal inflammation as a consequence of an impaired ability to handle enteric bacterial pathogens.

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