Gesa J Albers, Christina Michalaki, Patricia P Ogger, Amy F Lloyd, Benjamin Causton, Simone A Walker, Anna Caldwell, John M Halket, Linda V Sinclair, Sarah H Forde, Cormac McCarthy, Timothy S C Hinks, Clare M Lloyd, Adam J Byrne
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引用次数: 0
摘要
肺是一个动态的微环境,气道巨噬细胞(AMs)是驻肺的主要巨噬细胞。巨噬细胞决定着组织稳态和免疫激活之间的平衡,因此具有相互矛盾的功能,既能维持耐受性和组织稳态,又能引发强烈的炎症反应。新的证据强调了巨噬细胞功能与细胞新陈代谢之间的联系。然而,这些过程在组织驻留的特化巨噬细胞群(如在呼吸道中发现的巨噬细胞群)中的功能重要性仍未得到充分阐明。在这里,我们揭示了糖酵解是巨噬细胞的一个基本途径,它同时调节着肺的稳态和对吸入过敏原的反应。利用体内巨噬细胞特异性靶向和多组学方法,我们确定了AMs中的糖酵解活性是在体内平衡过程中抑制2型(T2)免疫所必需的。暴露于包括屋尘螨(HDM)在内的一系列常见空气过敏原会促进AM糖酵解,此外,AM特异性糖酵解抑制会改变气道炎症和HDM驱动的体内气道代谢适应。此外,与未致敏的哮喘对照组相比,过敏原致敏的哮喘患者的气道代谢发生了深刻变化。最后,我们发现过敏原驱动的小鼠 AM 糖酵解作用依赖于 TLR2。因此,我们的研究结果表明,AM 中的糖酵解、AM 介导的体内平衡过程和肺部的 T2 免疫反应之间存在直接关系。这些数据表明,糖酵解对 AM 的可塑性至关重要。根据不同的免疫环境,AM-糖酵解需要发挥稳态活性,但一旦被过敏原激活,AM-糖酵解就会影响炎症反应。因此,精确调节AMs中的糖酵解活性对于保持肺稳态和调节气道炎症至关重要。
Airway macrophage glycolysis controls lung homeostasis and responses to aeroallergen.
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.
期刊介绍:
Mucosal Immunology, the official publication of the Society of Mucosal Immunology (SMI), serves as a forum for both basic and clinical scientists to discuss immunity and inflammation involving mucosal tissues. It covers gastrointestinal, pulmonary, nasopharyngeal, oral, ocular, and genitourinary immunology through original research articles, scholarly reviews, commentaries, editorials, and letters. The journal gives equal consideration to basic, translational, and clinical studies and also serves as a primary communication channel for the SMI governing board and its members, featuring society news, meeting announcements, policy discussions, and job/training opportunities advertisements.