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

Lead Research Organisation: University of Manchester
Department Name: School of Biological Sciences


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.


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Studentship Projects

Project Reference Relationship Related To Start End Student Name
MR/N013751/1 30/09/2016 29/09/2025
1916581 Studentship MR/N013751/1 30/09/2017 29/09/2021 Hannah Smith
Description Invited to speak at the 2017 National Science Festival "Pint of Science. Discussed The many moods of macrophages and how we can educated them to become healing rather damaging 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 50 members of the general public attended my Pint of Science talk where I described the many moods of macrophages and how we can educated them to become healing rather damaging. The event was held in the Klondyke Club in Levenshulme, Manchester and lead to some really great discussion and interesting questions over a pint of beer!
Year(s) Of Engagement Activity 2017
Description Museum science events 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Stands in the museum/local library where we talk to the public about our work and try to get them interested in biology. There are games for the children and samples for everyone to look at.
Year(s) Of Engagement Activity 2018,2019