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

摘要 Th 2应答失调是过敏性疾病发病机制的核心。中心法则是 经典的树突状细胞（cDC）是Th 2细胞的主要驱动者，这已经在很大程度上使用 靶向CD 11 c的策略，CD 11 c虽然由cDC表达，但也存在于其他细胞如单核细胞， 巨噬细胞我们的数据表明MafB+ CD 11 c +MHCIIhi间质细胞群的存在。 巨噬细胞（MHCIIhi IM），显著诱导响应屋尘螨（HDM）。因此，以前 针对cDC的策略可能共同靶向这些IM。利用特定目标，我们首次展示了 这些MHCIIhi IM是驱动气道中过敏原诱导的Th 2应答的中心。我们的数据表明 Th 2免疫的发展，长期以来一直是树突状细胞的范围，现在包括一个中央免疫系统。 MHCIIhi IM的角色。同样，我们也发现HLA-DRhi巨噬细胞在患者组织中升高， 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 方法中，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过程中IM积累，强烈表明VG神经元 有助于IM积聚以响应过敏原。因此，迷走神经节-神经肽-IM串扰起作用， 作为介导气道变态反应的潜在轴。探索这些细胞的生物能量学，我们发现MHCIIhi IM 似乎严重依赖于葡萄糖代谢的功能。它们表达最高水平的糖酵解- 相关基因，并损害葡萄糖代谢降低他们的能力，采取HDM，一些没有看到 在体内cDC中，表明IM在其对抗原糖酵解的依赖性方面与cDC本质上不同， 呈现功能。此外，阻断糖酵解减少嗜酸性粒细胞、Th 2细胞和IgE，但不减少嗜中性粒细胞， cDC或IL-13+ ILC。最后，我们发现HDM诱导的MHCIIhi IM也高度富集了α-淀粉酶-1， M2 macs的典型标志物，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Th 2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、ST 2和消除IL-33受体的作用。 IL-33信号传导影响arg 1 + IM，但不影响总IM。此外，我们发现神经元输入诱导ST 2 表达，从而使macs对IL-33敏感。总之，我们假设HDM诱导的IL-33促进了M2样细胞凋亡。 极化状态，有利于驱动Th 2应答的MHCIIhi顶-T细胞对话。为了验证这一点，我们建议 目的：1）检查调节MHCIIhi IM积累的神经元通路，2）检查MHCIIhi IM的糖酵解程序， MHCIIhi IM，并测试其对Th 2应答的需求，3）测试驱动替代性免疫应答的神经肽-IL-33轴， MHCIIhi IM极化有利于Th 2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.