Lipid Mediators and the Regulation of Macrophage Function and Colitis.

摘要

The maintenance of balanced immune responses is vital to the health of an individual. This is of particular importance in the intestine, as it represents a vast immunological challenge due to the enormous antigenic potential of the commensal microbiota. The body has therefore developed a number of homeostatic strategies to ensure that inflammatory reactions are freely able to clear foreign material such as bacteria in a manner that is self-limiting. The dysregulation of these processes, however, can lead to the development of chronic diseases such as inflammatory bowel disease (IBD).;A cell type that plays a vital role in maintaining this homeostasis is the macrophage. In this thesis, I have demonstrated how the phagocytosis of bacteria is enhanced in these cells by lipoxins, a family of lipid mediators that are involved in inducing the resolution of inflammation. This phenomenon was associated with a concomitant decrease in pro-inflammatory mediator production, suggesting that lipoxins are able to induce a macrophage phenotype that is geared towards eliminating any residual infections at the end stages of inflammation, and return tissues to sterile homeostasis.;The functions of lipoxin were also found to be dependent on the signalling molecule phosphoinositide 3-kinase p110gamma (PI3Kgamma). This enzyme has previously been shown to be involved in the recruitment of leukocytes to inflamed tissues, and thus its inhibition or genetic knock-out has been shown to effectively treat a number of mouse models of inflammatory disease. We show here that mice deficient in PI3Kgamma are initially protected from acute experimental colitis induced by the haptenizing agent trinitrobenzene sulfonic acid (TNBS), but fail to heal properly due to an inability to clear bacteria that have infected the colonic tissue.;Taken together, these studies highlight the importance of bacterial clearance from inflamed tissues, and suggest that the development of novel anti-inflammatory therapies that promote, rather than hinder the antimicrobial functions of phagocytes such as macrophages could be of use in the treatment of IBD.