Airway macrophage glycolysis controls lung homeostasis and responses to aeroallergen
Year: 2024
Type: article
Abstract: The lungs represent a dynamic microenvironment where airway macrophages (AMs) are the major lung-resident macrophages. AMs dictate the balance between tissue homeostasis and immune activation and thus have contradictory functions by maintaining tolerance and tissue homeostasis, as well as initiating strong inflammatory responses. Emerging evidence has highlighted the connection between macrophage function and cellular metabolism. However, the functional importance of these processes in tissue-resident specialized macrophage populations such as those found in the airways, remain poorly elucidated. Here, we reveal that glycolysis is a fundamental pathway in AMs which regulates both lung homeostasis and responses to inhaled allergen. Using macrophage specific targeting in vivo, and multi-omics approaches, we determined that glycolytic activity in AMs is necessary to restrain type 2 (T2) immunity during homeostasis. Exposure to a range of common aeroallergens, including house dust mite (HDM), drove AM-glycolysis and furthermore, AM-specific inhibition of glycolysis altered inflammation in the airways and HDM-driven airway metabolic adaptations in vivo. Additionally, allergen sensitised asthmatics had profound metabolic changes in the airways, compared to non-sensitised asthmatic controls. Finally, we found that allergen driven AM-glycolysis in mice was TLR2 dependent. Thus, our findings demonstrate a direct relationship between glycolysis in AMs, AM-mediated homeostatic processes, and T2 immune responses in the lungs. These data suggest that glycolysis is essential for the plasticity of AMs. Depending on the immunological context, AM-glycolysis is required to exert homeostatic activity but once activated by allergen, AM-glycolysis influences inflammatory responses. Thus, precise modulation of glycolytic activity in AMs is essential for preserving lung homeostasis and regulating airway inflammation.
Source: Mucosal Immunology
Institutions: Imperial College London, University of Dundee, King's College London, University College Dublin, University Hospital Southampton NHS Foundation Trust, National Institute for Health and Care Research, University of Oxford, NIHR Southampton Respiratory Biomedical Research Unit, University of Southampton
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
Awards: G1519649567, Signalling pathways that control T cell metabolism and T cell fate, G3271205087, The role of interleukin-17 in airway inflammation in asthma., Defining the innate-like mucosal T cell response to bacterial infection in airways disease, Fluorescence activated cell sorting for cell biology and immunology, Epithelial-Alveolar Macrophage interactions underlying the regulation of allergic inflammation and remodelling ., A dual electron and X-ray analytic approach to defect-engineered materials, G9000196093
OpenAlex ID: W4403532430