Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, Munich, Germany.
Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Moscow, and Sirius University of Science and Technology, Sochi, Russia.
J Allergy Clin Immunol. 2022 Jun;149(6):2078-2090. doi: 10.1016/j.jaci.2021.11.026. Epub 2021 Dec 30.
Infectious agents can reprogram or "train" macrophages and their progenitors to respond more readily to subsequent insults. However, whether such an inflammatory memory exists in type 2 inflammatory conditions such as allergic asthma was not known.
We sought to decipher macrophage-trained immunity in allergic asthma.
We used a combination of clinical sampling of house dust mite (HDM)-allergic patients, HDM-induced allergic airway inflammation in mice, and an in vitro training setup to analyze persistent changes in macrophage eicosanoid, cytokine, and chemokine production as well as the underlying metabolic and epigenetic mechanisms. Transcriptional and metabolic profiles of patient-derived and in vitro trained macrophages were assessed by RNA sequencing or metabolic flux analysis and liquid chromatography-tandem mass spectrometry analysis, respectively.
We found that macrophages differentiated from bone marrow or blood monocyte progenitors of HDM-allergic mice or asthma patients show inflammatory transcriptional reprogramming and excessive mediator (TNF-α, CCL17, leukotriene, PGE, IL-6) responses upon stimulation. Macrophages from HDM-allergic mice initially exhibited a type 2 imprint, which shifted toward a classical inflammatory training over time. HDM-induced allergic airway inflammation elicited a metabolically activated macrophage phenotype, producing high amounts of 2-hydroxyglutarate (2-HG). HDM-induced macrophage training in vitro was mediated by a formyl peptide receptor 2-TNF-2-HG-PGE/PGE receptor 2 axis, resulting in an M2-like macrophage phenotype with high CCL17 production. TNF blockade by etanercept or genetic ablation of Tnf in myeloid cells prevented the inflammatory imprinting of bone marrow-derived macrophages from HDM-allergic mice.
Allergen-triggered inflammation drives a TNF-dependent innate memory, which may perpetuate and exacerbate chronic type 2 airway inflammation and thus represents a target for asthma therapy.
传染因子可重新编程或“训练”巨噬细胞及其前体细胞，使其更易于对后续刺激做出反应。然而，在 2 型炎症性疾病（如过敏性哮喘）中是否存在这种炎症记忆尚不清楚。
我们旨在阐明过敏性哮喘中巨噬细胞的训练免疫。
我们结合了临床采样（尘螨 [HDM] 过敏患者）、HDM 诱导的小鼠过敏性气道炎症和体外训练设置，以分析巨噬细胞花生四烯酸、细胞因子和趋化因子产生的持续变化，以及潜在的代谢和表观遗传机制。通过 RNA 测序或代谢通量分析和液相色谱-串联质谱分析分别评估患者来源和体外训练的巨噬细胞的转录和代谢谱。
我们发现，从 HDM 过敏小鼠或哮喘患者的骨髓或血液单核细胞祖细胞分化而来的巨噬细胞在受到刺激时表现出炎症转录重编程和过度介质（TNF-α、CCL17、白三烯、PGE、IL-6）反应。HDM 过敏小鼠的巨噬细胞最初表现出 2 型印迹，随着时间的推移逐渐向经典炎症训练转变。HDM 诱导的过敏性气道炎症引起代谢激活的巨噬细胞表型，产生大量 2-羟基戊二酸（2-HG）。体外 HDM 诱导的巨噬细胞训练是通过形式肽受体 2-TNF-2-HG-PGE/PGE 受体 2 轴介导的，导致具有高 CCL17 产生的 M2 样巨噬细胞表型。etanercept 阻断 TNF 或髓细胞中 Tnf 的基因缺失可防止 HDM 过敏小鼠骨髓来源的巨噬细胞产生炎症印迹。
过敏原触发的炎症驱动 TNF 依赖性先天记忆，这可能会持续和加重慢性 2 型气道炎症，因此代表了哮喘治疗的一个靶点。
