Neuronally-driven accumulation of glycolytic MafB+MHCIIhi IMs drive airway allergy

神经元驱动的糖酵解 MafB MHCIIhi IM 积累导致气道过敏

基本信息

批准号：
10736048
负责人：
Stephane Lajoie
金额：
$ 60.73万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-21 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736048
关键词：
Address Afferent Neurons Allergens Allergic Allergic Disease Allergic inflammation Antigen Presentation Automobile Driving Bioenergetics Cells Data Dendritic Cells Development Exposure to Frequencies Ganglia Genes Genetic Glucose Glycolysis Goals Human Hypersensitivity ITGAX gene IgE Immunity Impairment In Vitro Inflammation Inflammatory Response Interleukin-13 Knockout Mice Ligands Lung Macrophage Macrophage-1 Antigen Mediating Metabolic Modality Molecular Mus Myeloid Cells Nasal Polyps Neurons Neuropeptide Receptor Neuropeptides PROKR1 gene Pathogenesis Pathway interactions Patients Phenotype Population Prevalence Pulmonary Inflammation Pyroglyphidae Regulation Role Signal Transduction Source T-Lymphocyte Testing Th2 Cells Time Tissues allergic airway disease allergic airway inflammation allergic response arginase cell type comparison control cytokine eosinophil genetic approach glucose metabolism in vivo interstitial metabolic profile monocyte nerve supply neurotransmission novel therapeutics programs public health relevance receptor response selective expression single-cell RNA sequencing

项目摘要

ABSTRACT Dysregulated Th2 responses are central to the pathogenesis of allergic diseases. The central dogma is that classical dendritic cells (cDCs) are the primary drivers of Th2 cells, this has been largely established using strategies targeting CD11c, which while expressed by cDCs, is also present by other cells like monocytes and macrophages. Our data demonstrates the existence of population of MafB+CD11c+MHCIIhi interstitial macrophages (MHCIIhi IMs), significantly induced in response to house dust mite (HDM). Thus, previous strategies aimed at cDCs may have co-targeted these IMs. Using specific targeting, we show for the first time that these MHCIIhi IMs are central to driving allergen-induced Th2 responses in the airways. Our data propose that the development of Th2 immunity, which has long been the purview of dendritic cells, now includes a central role for MHCIIhi IMs. Consistently, we also find that HLA-DRhi macrophages are elevated in the tissue of patients with allergic nasal polyps. Although their regulation during allergy is not understood. Using chemogenetic approaches, we find that pulmonary innervation emanating from the vagal ganglia (VG) directly induces MHCIIhi IM accumulation during HDM-induced allergic airway inflammation, strongly indicating that VG neurons contribute to IM accumulation in response to allergen. Therefore, vagal ganglion-neuropeptide-IM crosstalk acts as a potential axis mediating airway allergy. Exploring the bioenergetics of these cells, we find that MHCIIhi IMs appear to rely heavily on glucose metabolism for function. They express the highest levels of glycolysis- associated genes, and impairing glucose metabolism decreases their ability to take up HDM, something not seen in cDCs in vivo, suggesting that IMs are intrinsically different than cDCs in their reliance on glycolysis for antigen- presenting function. Further, blocking glycolysis reduces eosinophils, Th2 cells, and IgE, but not neutrophils, cDCs, or IL-13+ILCs. Lastly, we found that HDM-elicited MHCIIhi IMs are also highly enriched for arginase-1, a canonical marker of M2 macs, more so than any other myeloid cell type, including AMs. We postulate that innate cytokines act as microenvironmental signals that condition IMs, favoring the development of Th2 cells. Seeking to understand this mechanism, we found that IMs express high levels of the IL-33 receptor, ST2 and eliminating IL-33 signaling impacts arg1+IMs, but not total IMs. Moreover, we found that neuronal inputs induce ST2 expression, thus sensitizing macs to IL-33. In sum, we hypothesize that HDM-elicited IL-33 promotes an M2-like polarization state, favoring an MHCIIhi IM-T cell dialog that drive Th2 responses. To examine this, we propose to: 1) Examine the neuronal pathways regulating MHCIIhi IM accumulation, 2) Examine the glycolytic program of MHCIIhi IMs, and test its requirement for Th2 responses, 3) test neuropeptide-IL-33 axis that drives alternative MHCIIhi IMs polarization favoring Th2 development.

抽象的 TH2反应失调对于过敏性疾病的发病机理至关重要。中心教条是经典的树突状细胞（CDC）是Th2细胞的主要驱动因素，这在很大程度上是使用的针对CD11C的策略虽然由CDC表示，但也由单核细胞（如单核细胞）和巨噬细胞。我们的数据证明了MAFB+CD11C+MHCIIHI间隙的存在巨噬细胞（MHCIIHI IMS），响应房屋尘螨（HDM）而显着诱导。因此，以前针对CDC的策略可能已将这些IMS靶向。使用特定的目标，我们首次显示这些MHCIIHI IMS对于驱动过敏原诱导的TH2响应至关重要。我们的数据提出了长期以来一直是树突状细胞的权限的Th2免疫的发展现在包括一个中央 Mhciihi ims的角色。一致地，我们还发现患者组织中HLA-DRHI巨噬细胞升高与鼻息肉过敏。尽管尚不理解它们在过敏过程中的调节。使用化学发生方法是，我们发现从迷走神经节（VG）发出的肺神经直接引起Mhciihi IM在HDM引起的过敏性气道炎症期间积累，强烈表明VG神经元响应过敏原而促进IM积累。因此，迷走神经节神经毒肽-IM串扰行为作为介导气道过敏的潜在轴。探索这些细胞的生物能学，我们发现Mhciihi ims 似乎严重依赖葡萄糖代谢来进行功能。他们表达最高水平的糖酵解水平相关的基因和损害葡萄糖代谢可降低其占HDM的能力，这是未见的在体内CDC中，这表明IMS与CDC在依赖糖酵解的抗原质量依赖中本质上不同呈现功能。此外，阻断糖酵解可减少嗜酸性粒细胞，Th2细胞和IgE，但不是中性粒细胞， CDC或IL-13+ILC。最后，我们发现HDM吸收的MHCIIHI IMS也非常富集精氨酸酶-1 M2 MAC的规范标记，比任何其他髓样细胞类型都要多，包括AM。我们假设那个先天细胞因子充当条件IM的微环境信号，有利于Th2细胞的发展。寻求为了理解这种机制，我们发现IMS表达高水平的IL-33受体，ST2和消除 IL-33信号传导会影响arg1+ims，但不影响IMS。此外，我们发现神经元输入诱导ST2 表达，从而使MAC对IL-33敏感。总而言之，我们假设HDM引起的IL-33促进了M2样极化状态，有利于驱动Th2响应的MHCIIHI IM-T细胞对话框。为了审查这一点，我们提出了至：1）检查调节MHCIIHI IM积累的神经元途径，2）检查的糖酵解程序 mhciihi ims，并测试其对TH2响应的需求，3）测试驱动替代方案的Neuropeptide-IL-33轴 Mhciihi IMS极化有利于Th2发展。