Chew, TS; (2015) An investigation into the role of optineurin in macrophage-mediated acute antibacterial response in inflammatory bowel disease. Doctoral thesis , UCL (University College London).

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Abstract

Crohn’s disease (CD) is now recognised to be due to defective host responses to bacteria in genetically susceptible individuals. Others in our research group previously found defective neutrophil recruitment, bacterial clearance and monocyte-derived macrophage (MDM) proinflammatory cytokine secretion in CD. To investigate the defective cytokine secretion, we performed transcriptomic analysis and identified reduced MDM optineurin (OPTN) expression in 10% CD patients. Here, I show that macrophages stimulated with E. coli, bacterial Toll-like and NOD-like receptor ligands upregulate OPTN, a Golgi complex protein that regulates vesicle transport. In vitro, Optn-/- bone marrow-derived macrophages (BMDM) stimulated with E. coli secrete significantly lower levels of proinflammatory TNF and IL6 cytokines, which is normalised to wildtype levels on addition of lysosomal function inhibitors. In vivo, Optn-/- mice develop a more severe Citrobacter colitis with greater mortality, an early defective neutrophil recruitment to the bowel and lower levels of serum proinflammatory cytokines. The Optn-/- mice also demonstrated a similar phenotype of defective neutrophil recruitment and lower serum proinflammatory cytokines in an E. coli-induced peritonitis. These results indicate that the low OPTN expression originally identified in CD macrophages has likely contributed to an attenuated antibacterial response, which potentially led to the development of bowel inflammation.

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