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

Abstract

Macrophages are vital components of the innate immune system, an extremely adaptable myeloid cell that acts as both detector and first responder to infection and wounding. While these cells are found in every organ in the body, their role as both protectors and aggressors can be varied and distinct depending on the context of their surroundings and complex incoming signals, making these cells extremely variable in their responses to stimuli. The origin of the tissue-resident macrophage is a complex puzzle that may be drastically different between compartments of an organism. Traditionally, macrophage populations in the gut where thought to be almost entirely supplied by incoming monocytes from the bone marrow. However, more recent work has shown there is a population of self-replicating tissue-resident macrophage that may have originated in the embryo. Using a CCR2-/- mouse, we have shown that there is a level of redundancy in CCR receptors in monocyte recruitment into the intestine during Trichuris muris infection. Additionally, utilising a mouse model with a compound deletion of CCR receptors (CCR1, CCR2, CCR3 and CCR5), which together controls monocytic and eosinophilic recruitment into tissues, we have found a population of resident macrophages still present in the intestine during T. muris-driven inflammation. Additionally, the quality and type of macrophage activation can have a profound effect on the outcome of infection and disease. Macrophage activation has traditionally been divided into pro-inflammatory “M1” cells and anti-inflammatory “M2” cells. While M1 cells have been well studied in the context of infection with microorganisms, M2 cells, a prominent marker of helminth and allergic responses, are less well understood. A distinct but understudied factor of the M2 cells are the characteristic markers that are used to distinguish these cells from their M1 counterparts. Using mouse models of Trichuris muris infection, an inducer of M2 cells in the gut, this project explores the differing roles of two prominent markers of M2 cells, RELMα and Ym1. Expression of these molecules in T. muris infection is dynamic and they appear to be differentially regulated between different tissues and in different cell types. While depleting Ym1 during infection accelerated expulsion of T. muris from the gut, the more abundant protein RELMα appears to be mostly dispensable for resistance to this parasite. Taken together, the work presented in this thesis provides evidence that M2 macrophage products are more than just markers of Th2 inflammation, but rather complex modulators of the Th2 response in their own right. This project provides evidence that both Ym1 and RELMα are capable of restraining the Th2 inflammation in response to intestinal infection. Additionally, at least for Ym1, there is a temporal aspect to its ability to control the immune response, possibly as an evolutionary brake on the late stages of infection in order to preserve tissue integrity against large multicellular helminth infection. 

Date of Award	1 Aug 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Tara Sutherland (Supervisor), Kathryn Else (Supervisor) & Judi Allen (Supervisor)