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

摘要 Th2反应失调是过敏性疾病发病机制的核心。核心的教条是 经典树突状细胞(CDCs)是Th2细胞的主要驱动力，这在很大程度上是通过 针对CD11c的策略，CD11c虽然由CDC表达，但也存在于其他细胞，如单核细胞和 巨噬细胞。我们的数据证明了MafB+CD11c+MHCIIi间隙的存在 巨噬细胞(MHCIIhi IMS)，对屋尘螨(HDM)有显著的诱导作用。因此，以前的 针对疾病预防控制中心的战略可能共同瞄准了这些IM。使用特定的目标，我们首次展示了 这些MHCIIHIMS在驱动变应原诱导的呼吸道Th2反应中起核心作用。我们的数据显示 Th2免疫的发展，长期以来一直是树突状细胞的范围，现在包括一个中央 MHCIIhi IMS的角色。我们还一致地发现，患者组织中的人类白细胞抗原-DRHI巨噬细胞升高。 患有过敏性鼻息肉。虽然它们在过敏过程中的调节还不清楚。使用化学发生学 方法：我们发现来自迷走神经节(VG)的肺神经支配直接诱导MHCIIHI。 在HDM诱导的过敏性呼吸道炎症过程中IM的积聚，强烈表明VG神经元 促进IM积聚，以应对过敏原。因此，迷走神经节-神经肽-IM相声起作用 作为一个潜在的轴，介导呼吸道过敏。通过对这些细胞的生物能量学的研究，我们发现MHCIIhi IMS 似乎严重依赖于葡萄糖代谢来发挥作用。它们表达最高水平的糖酵解- 相关基因和糖代谢受损会降低他们摄取HDM的能力，这是未曾见过的 在体内的CDCs中，表明IMS与CDCs在本质上不同，它们依赖糖酵解来获得抗原- 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。 CDCs，或IL-13+ILCs。最后，我们发现HDM诱导的MHCIIhi IMS也高度富含精氨酸酶-1，a M2MACs的典型标志，比包括AM在内的任何其他髓系细胞类型更具代表性。我们假设这是天生的 细胞因子作为微环境信号调节IMS，有利于Th2细胞的发育。寻找 为了了解这一机制，我们发现IMS表达高水平的IL-33受体ST2和清除 IL-33信令影响Arg1+IMS，但不影响整个IMS。此外，我们发现神经元的输入诱导了ST2 表达，从而使Mac对IL-33敏感。总而言之，我们假设HDM诱导的IL-33促进类似M2的 偏振状态，有利于MHCIIhi IM-T细胞对话，驱动Th2反应。为了研究这一点，我们建议 为了：1)研究调节MHCIIHI IM蓄积的神经元通路；2)研究MHCIIHI-IM的糖酵解程序 MHCIIHI IMS，并测试其对Th2反应的要求；3)检测驱动替代的神经肽-IL-33轴 MHCIIHIMS极化有利于Th2的发育。

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.