Defining local and systemic pathways that influence allergic lung inflammation

Abstract

Asthma is one of the most common chronic inflammatory disorders in the world, resulting in significant disability, poor quality of life and healthcare costs. The inflammatory response in asthma primarily involves aberrant Th2 responses and eosinophil infiltration in the airways. However, patients also show evidence of non-Th2-mediated asthma, characterised by airway neutrophilia and Th1/Th17 responses. Current treatment for the disease can induce long-term side effects and patients lack more tailored and effective therapies. Moreover, there is increasing evidence for asthmatic patients developing concomitant chronic inflammation of the gut. There is therefore the necessity to further investigate the mechanisms underlying the development of asthma and whether inter-organ communication may be relevant in its etiology with the aim of finding alternative therapeutic targets. Using a murine model of acute allergic asthma, the results presented in this thesis describe a system in which different immune compartments can be interconnected with each other. Focussing on eosinophils, we show that these cells can adapt to the characteristics of the tissue microenvironment where they reside by acquiring features that may be correlated with homeostatic or pro-inflammatory properties. Pro-inflammatory features of eosinophils were associated with a metabolic reprogramming of these cells, which was supported by factors enriched in the lung environment, such as IL-33, GM-CSF and IL-5. We found that lung pro-inflammatory eosinophils and neutrophils expressed GPR109a and that agonists of this receptor, including the metabolite butyrate and the vitamin niacin, had anti-inflammatory effects in both eosinophilic and neutrophilic asthma. Eosinophil and lymphocyte populations in the gut were also affected by the ongoing lung inflammatory responses. Eosinophil heterogeneity and acquisition of pro-inflammatory features was present in the small intestine, whereas T cell- and type-2 innate lymphoid cell-mediated Th2 responses dominated the large intestine. We provide evidence for T cell recirculation as well as structural, biochemical and microbial changes in the large intestine, that may rewire the gut metabolic machinery to restore body homeostasis. In summary, this work highlights GPR109a as a potentially exciting target for the treatment of Th2 and non-Th2 asthma and provides additional mechanistic insights into inter-organ communication. These findings may inform unappreciated therapeutic interventions that could impact treatment of asthma.

Date of Award	1 Aug 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Tara Sutherland (Supervisor), Tracy Hussell (Supervisor), John Grainger (Supervisor) & Joanne Konkel (Supervisor)