Defining functional roles of alternatively activated macrophage-derived products in infection-driven intestinal inflammation and tissue repair.

Infections with gut-dwelling parasitic nematodes drive strong type 2 immune responses that are important for rapid parasite clearance and tissue repair following worm invasion. Type 2 immunity associates closely with the development of alternatively activated, or M2 macrophages, originally defined in vitro as developing in the context of the type 2 cytokine IL-4. RELM-alpha and chitinase-like proteins (CLPs) like Ym1 represent some of the most abundant effector molecules produced by M2 macrophages. Expression of Ym1 and RELM-alpha, correlate strongly with inflammation and pathology, highlighting the importance of these molecules in host responses to pathogens. However, there is remarkably little known about the functions of Ym1 and RELM-alpha, particularly in the context of large intestinal inflammation. Defining key factors that regulate tissue inflammation will be critical for developing strategies that promote mucosal healing in the context of tissue pathology.

Thus, defining the function(s) of M2-derived molecules is important, with therapeutic relevance to many pathologies that feature persisting inflammation, such as inflammatory bowel disease and chronic wounds.

We have recently shown that M2-like macrophages, expressing the M2-derived molecules Ym1 and RELM-alpha, develop post infection with the intestinal nematode parasite Trichuris muris. Interestingly, the M2-like macrophages only emerge in gut tissue after worm expulsion, implying a role in the repair of tissue, damaged by both the physical presence of the infection and by collateral damage during the protective immune response which expels the parasite. Additionally, our data links both Ym1 and RELM-alpha to accelerated tissue repair through the control of collagen fibril assembly in the skin and lung.

The precise and predictable emergence of the M2-like macrophage in the T. muris mouse model allows us to address the undefined functions of Ym-1and RELM-alpha in vivo in the inflamed intestine, by depleting these mediators individually or collectively. We will achieve this using a combination of gene targeted mice, including the generation of a novel transgenic, and in vivo antibody treatment post infection, to identify any defects in the tissue reparative process in the absence of these mediators.

The project will utilise a range of contemporary methodologies in immunology, including in vivo models of disease, transgenic mouse methodologies, multi-colour flow cytometry, cytokine bead arrays, tissue bioimaging and molecular biology. As such the student will develop an exceptional skills base, in addition to being mentored by a highly experienced academic team.