Characterising the peritoneal and hepatic response to enteric nematode infection

Abstract

Following infection of barrier surfaces, such as the gut, it is increasingly recognised that the stressed organ can induce responses in distal tissues. However, the mechanisms driving these events, and the signals experienced by different tissues, are only just being elucidated; particularly in the setting of type 2 inflammation. Utilising a gastro-intestinal helminth infection model of type 2 inflammation (Heligmosomoides polygyrus), this thesis describes the development of a mixed Th1/Th2 extra-intestinal response within two sites anatomically-associated with the gut - the liver and the peritoneal cavity. Here we show the infiltration of various myeloid immune cell subsets following infection, and detail how their tissue localisation and polarisation change over time. Using the canonical IL-4/IL-13-polarised macrophage markers RELM-a, PD-L2, and Ym1, alongside the interferon-inducible gene Sca-1, we detail the tissue dependent polarisation of macrophages at these two sites. During infection, monocyte-derived CD64+ small peritoneal macrophages ingress into the peritoneal cavity and co-express RELM-a and Sca-1, suggestive of concurrent IL-4/IL-13 and interferon education. While in the liver, tissue resident macrophage and infiltrating monocyte marker expression is limited to those associated with interferon education. Employing transgenic mice and antibody blockade, we show the expression of these markers is crucially dependent on IL-4/IL-13 and interferon signalling, signifying that the innate immune cells within the liver and peritoneal cavity experience these signals simultaneously during Th2-driving gut infection. Finally, ex vivo stimulation of peritoneal macrophages and in vivo investigation in the liver and peritoneal cavity finds that this Th1/Th2 immune response modulates the expression of CCL2, CXCL9, CXCL10, and CXCL13 in a myeloid cell and tissue dependent manner. Collectively our results demonstrate that during the development of gastro-intestinal type 2 immunity, macrophages in distal tissues experience unappreciated type I IFN and IFN-g signals that may impact their function. Targeting interferon-signalling could provide a novel approach to modifying system-wide immune responses in type 2 inflammation.

Date of Award	31 Dec 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Judi Allen (Supervisor), John Grainger (Supervisor) & Joanne Konkel (Supervisor)