Investigation of the Effects of Interleukin-27 on Human Innate Immune Responses

Abstract

Human macrophages and neutrophils are key cells of the innate immune system. Chronic inflammatory diseases, such as inflammatory bowel disease (IBD), are characterised by dysregulated macrophage and neutrophil function. Regulation of macrophage and neutrophil function represents a viable strategy to attenuate chronic inflammatory diseases. Interleukin (IL)-27 is a pleiotropic cytokine which can promote immunosuppressive responses by downregulating Th2 and Th17 proinflammatory responses whilst promoting IL-10 expression from regulatory T-cells. In this thesis, the effects of IL-27 upon human macrophages and neutrophils, isolated from human whole blood, are defined.

IL-27 induced significant upregulation of the chemokines CXCL9 and CXCL10 in human neutrophils and monocyte-derived macrophages. Increased CXCL9 and CXCL10 gene expression translated to increased CXCL9 and CXCL10 protein in the supernatant of IL-27 stimulated macrophages; no CXCL9 or CXCL10 protein was detected in the supernatant of IL-27 stimulated neutrophils. IL-27 significantly increased MHCII expression in monocyte-derived macrophages whilst significantly downregulating cyclooxygenase-2 (COX2), mannose receptor C-type 1 (MRC1), IL-1β and IL-10. Phagocytosis of E. coli was downregulated in IL-27 stimulated macrophages. Proteomic analysis of IL-27 stimulated macrophages and neutrophils allowed a broader study in a discovery science approach. Trends were drawn from the proteomic analysis which include an increased interferon signature in IL-27 stimulated macrophages, as indicated by an increase in guanylate binding protein (GBP)-1 and interferon regulatory factor (IRF)-8, and a regulation of mitochondrial function in neutrophils, as indicated by a reduction in isocitrate dehydrogenase subunit beta and aspartate/glutamate antiporter.

Collectively, the findings in this thesis present novel and original data, demonstrating an ability for IL-27 to regulate the human innate immune system through changes to the function of human macrophages and neutrophils. Therefore, IL-27 may present a therapeutic treatment to regulate inflammatory diseases.

Date of Award	2024
Original language	English
Awarding Institution	University of Dundee
Supervisor	Mairi H McLean (Supervisor), Mahima Swamy (Supervisor) & Heather Wilson (Supervisor)