Ranson_whole_thesis.pdf (11.84 MB)
Inflammasome activity in the inflammatory bowel diseases
thesisposted on 2023-05-28, 10:00 authored by Nicole RansonNicole Ranson
Ulcerative colitis (UC) and Crohn's disease (CD) are characterised by chronic and recurrent inflammation of the gastrointestinal tract. The development of Inflammatory Bowel Diseases (IBD) is regarded as a multifactorial disease process involving a combination of immune system defects and environmental influences, which occur in the genetically predisposed individual. In the gut, the multimolecular complex known as the inflammasome is a key mediator in regulating the host's immune response to invading pathogens and/or cellular stress. Formation of the inflammasome complex provides a platform for the caspase-1 dependent activation of the potent inflammatory cytokines, interleukin (IL)-1˜í‚â§ and IL-18. Dysregulation of the inflammasome complex is thought to contribute to IBD pathogenesis. Quantitative RT-PCR, RNA-sequencing, immunohistochemistry and immunofluorescence confocal microscopy were used to examine the mRNA expression and cellular localisation of inflammasome forming components in colonic biopsies obtained from IBD and control patients. Rosiglitazone induced NLRP6 expression was performed in the colonic cell lines, LS174T and HT29 to investigate the effect of NLRP6 on MUC2 expression. Novel findings from this research include the disease specific upregulation of NLRP6 in active ileal CD. The identification of a NLRP6 expressing goblet cell localised predominantly in the upper portion of the intestinal crypt. Repression of MUC2 expression with increased expression of NLRP6 in the human colorectal adenocarcinoma cell line, LS174T. The localisation of AIM2 to the intraepithelial lymphocytes and the reduced contribution of NLRP3-dependent caspase-1 to bioactive IL-1˜í‚â§ production in active UC. In conclusion, NLRP6 can now be considered a potential marker for distinguishing ileal CD from colonic CD and terminal ileum involved UC. Furthermore, results of this study will direct future work examining if there is a therapeutic benefit in switching off NLRP6 in active ileal CD, or blocking both caspase-1 and neutrophil-derived serine protease production of IL-1˜í‚â§ in active UC.
Rights statementCopyright 2018 the author Chapter 3 and 5 appears to be, in part, the equivalent of a pre-print version of an article published as: Ranson, N., Veldhuis, M., Mitchell, B., Fanning, S., Cook, A. L., Kunde, D., Eri, R., 2019. NLRP3 dependent and independent processing of interleukin (IL)-1˜í‚â§ in active ulcerative colitis, 20(1), 57. Copyright 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)