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 反应失调是过敏性疾病发病机制的核心。中心法则是经典树突状细胞 (cDC) 是 Th2 细胞的主要驱动因素，这在很大程度上是通过使用针对 CD11c 的策略，CD11c 虽然由 CDC 表达，但也存在于单核细胞和其他细胞中巨噬细胞。我们的数据表明 MafB+CD11c+MHCIIhi 间质群体的存在巨噬细胞（MHCIIhi IM），显着诱导响应屋尘螨（HDM）。因此，之前的针对CDC的策略可能同时针对这些IM。使用特定目标，我们首次展示这些 MHCIIhi IM 对于驱动呼吸道中过敏原诱导的 Th2 反应至关重要。我们的数据建议 Th2 免疫的发展长期以来一直是树突状细胞的权限，现在包括一个中枢 MHCIIhi IM 的作用。一致地，我们还发现患者组织中的 HLA-DRhi 巨噬细胞升高患有过敏性鼻息肉。尽管它们在过敏期间的调节尚不清楚。使用化学遗传学方法，我们发现迷走神经节（VG）发出的肺神经支配直接诱导 MHCIIhi 在 HDM 诱导的过敏性气道炎症期间 IM 积累，强烈表明 VG 神经元有助于响应过敏原而积累 IM。因此，迷走神经节-神经肽-IM 串扰起作用作为介导气道过敏的潜在轴。通过探索这些细胞的生物能学，我们发现 MHCIIhi IM 似乎严重依赖葡萄糖代谢来发挥功能。它们表达最高水平的糖酵解- 相关基因，并且葡萄糖代谢受损会降低它们吸收 HDM 的能力，这是未见的在体内 cDC 中，表明 IM 与 cDC 本质上不同，因为它们依赖于糖酵解来产生抗原。呈现功能。此外，阻断糖酵解会减少嗜酸性粒细胞、Th2 细胞和 IgE，但不会减少中性粒细胞， cDC，或 IL-13+ILC。最后，我们发现 HDM 引发的 MHCIIhi IM 也高度富集精氨酸酶 1，精氨酸酶 1 是一种 M2 mac 的典型标记，比任何其他骨髓细胞类型（包括 AM）更重要。我们假设先天的细胞因子作为调节 IM 的微环境信号，有利于 Th2 细胞的发育。寻求为了理解这一机制，我们发现 IM 表达高水平的 IL-33 受体 ST2 并消除 IL-33 信号传导影响 arg1+IM，但不影响总 IM。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。总之，我们假设 HDM 诱导的 IL-33 促进 M2 样极化状态，有利于驱动 Th2 反应的 MHCIIhi IM-T 细胞对话。为了检验这一点，我们建议 1) 检查调节 MHCIIhi IM 积累的神经元通路，2) 检查糖酵解程序 MHCIIhi IM，并测试其对 Th2 反应的要求，3) 测试驱动替代的神经肽-IL-33 轴 MHCIIhi IM 极化有利于 Th2 的发展。