Butyrate selectively inhibits metabolic reprogramming of inflammatory eosinophils in allergic asthma
Rossana Azzoni1, Tara Sutherland1, Tracy Hussell1, Joanne Konkel1, Yashaswini Kannan2, Edith Hessel3 and John Grainger1
1Faculty of Medicine, Biology and Health, University of Manchester, Lydia Becker Institute, Manchester,UK
2Adaptive Immunity Research Unit, Glaxosmithkline, Stevenage, UK
3 Mestag Therapeutics, London, UK
Background: Allergic asthma is characterised by dominant Th2 responses to innocuous environmental antigens, such as house dust mite (HDM), resulting in significant airway eosinophilia. Eosinophil activation exerts a central role in asthma pathogenesis through the release of cytotoxic granules and cytokines. As well as these effector functions, eosinophils have been shown to promote homeostatic responses at steady-state and disease, which may explain why eosinophil-targeted therapies have had mixed results. Two different populations of eosinophils have recently been identified in the lungs of murine models of allergic inflammation, and have been described as Siglec-FintCD11bint and Siglec-FhiCD11bhi eosinophils.
Aims: It is still not clear how Siglec-FintCD11bint and Siglec-FhiCD11bhi eosinophils originate, and further develop during allergic disease, how they are maintained, what their phenotype is and if specific factors mediate these processes. Therefore, our aim was to better define these mechanisms to understand whether we could bias towards targeting one population or the other from a therapeutic standpoint.
Methods: We have used a murine model of acute allergic airway inflammation induced by intranasal exposure to HDM. Sensitisation (day 0) with HDM was followed by 5 consecutive challenges (day 7-11) and euthanasia 24 hours after the last challenge.
Results: We detected Siglec-FintCD11bint and Siglec-FhiCD11bhi eosinophils in the lungs and blood of HDM-treated mice. We found that Siglec-FhiCD11bhi but not Siglec-FintCD11bint eosinophils contributed to the inflammatory response. This was mediated via enhanced CD98 expression and metabolic activity, which represented universal features of Th2 inflammatory responses. We also established that, following HDM administration, the short-chain fatty butyrate could specifically decrease levels of Siglec-FhiCD11bhi eosinophils as well as their metabolic activity in the lung and that this mechanism may be mediated by GPR109a. Thus, selective targeting of Siglec-FhiCD11bhi eosinophils and their metabolism may be beneficial in ameliorating allergic lung inflammation.