RELMalpha-expressing macrophages mediate host disease tolerance in mucosal infection

对微生物病原体的最佳寄主反应需要平衡有效的病原体杀灭 由病原体或宿主自身的免疫反应引起的局限性组织病理。 这种对宿主疾病的耐受现象在感染蠕虫的情况下尤其关键， 是一种大型寄生虫，可导致严重的组织损伤和炎症。使用鼠标 钩虫感染巴西尼波氏线虫模型的研究 分子(RELm)是一种高度分泌的蛋白质，可保护宿主免受潜在的致命伤害 感染导致的肺组织损伤以最佳钩虫杀灭为代价。我们的中央 假设RELMa是一种宿主疾病耐受机制，它改变了平衡 杀灭蠕虫可消退炎症，促进组织愈合。RELMa由免疫细胞表达 巨噬细胞等细胞和上皮细胞(EC)等非免疫细胞。在预赛中 利用骨髓嵌合体和巨噬细胞共培养的数据，我们鉴定了RELMa- 表达交替激活的巨噬细胞(AAMac)对NB的杀伤效率较低，但 相反，它可以抑制肺部炎症，促进组织修复。此外，我们生成唯一的 Argiase1/RELMa AAMac双重记者，揭示AMac异质性和牵连 RELMa AAMacs作为一种新的创面愈合巨噬细胞亚群。基于这些发现， 这项建议的重点是将新的细胞特异性RELMa KO/Report小鼠与功能 共培养试验和新的RELMa试剂描绘巨噬细胞RELMa的功能 蠕虫相互作用与粘膜组织愈合。在目标1中，我们将使用特定于细胞的RELMA KO/Report小鼠和过继细胞转移描绘RELMa来源的贡献 天然细胞(AAMac或嗜酸性粒细胞)或EC对NB的免疫和组织愈合。在目标2中，我们将 用AAMac双报告小鼠研究巨噬细胞-NB相互作用的RELMa调节， RELMa融合蛋白和封闭抗体，以及优化的共培养试验。在目标3中，我们 将使用3D肺支架和EC气液界面与AAMacs和 间充质干细胞以确定表达RELMa的AAMacs和ECs如何与 肺间质，有助于肺组织恢复。我们期待着更好地理解 RELMa在蠕虫感染中的有益与致病作用可指导治疗 加强抗蠕虫免疫的策略，同时限制病理性炎症和 促进组织愈合。我们的发现为交替激活的巨噬细胞提供了新的见解 生物学和巨噬细胞-基质细胞的相互作用，可广泛适用于解决 粘膜组织损伤和炎症是重大的公共卫生问题。

The optimal host response to microbial pathogens requires balancing effective pathogen killing with limiting tissue pathology caused by the pathogen or by the host’s own immune response. This host disease tolerance phenomenon is especially critical in infections with helminths, which are macroparasites that can cause severe tissue damage and inflammation. Using a mouse model of hookworm infection with Nippostrongylus brasiliensis (Nb), we identify Resistin-like molecule (RELM)a as a highly secreted protein that protects the host from potentially fatal infection-induced lung tissue damage at the expense of optimal hookworm killing. Our central hypothesis is that RELMa is a host disease tolerance mechanism that shifts the balance from helminth killing to resolution of inflammation and tissue healing. RELMa is expressed by immune cells such as macrophages and non-immune cells such as epithelial cells (EC). In preliminary data utilizing bone marrow chimeras and macrophage co-cultures, we identified that RELMa- expressing alternatively activated macrophages (AAMac) are less efficient at Nb killing, but instead dampen lung inflammation and promote tissue repair. Further, we generate unique Arginase1/RELMa AAMac dual reporters, that reveal AAMac heterogeneity and implicate RELMa+ AAMacs as a new wound healing macrophage subset. Based on these findings, the focus of this proposal is to combine novel cell-specific RELMa KO/reporter mice with functional co-culture assays and new RELMa reagents to delineate RELMa function in macrophage- helminth interactions and mucosal tissue healing. In Aim 1, we will employ cell-specific RELMa KO/reporter mice and adoptive cell transfers to delineate the contribution of RELMa derived from innate cells (AAMac or eosinophils) or EC to Nb immunity and tissue healing. In Aim 2, we will investigate RELMa regulation of macrophage-Nb interaction using AAMac dual reporter mice, RELMa fusion proteins and blocking antibodies, and optimized co-culture assays. In Aim 3, we will employ 3D lung scaffold and EC air-liquid interface co-cultures with AAMacs and mesenchymal stem cells to determine how RELMa-expressing AAMacs and ECs interact with the lung stroma and aid lung tissue recovery. We anticipate that a better understanding of the beneficial versus pathogenic effects of RELMa in helminth infection could guide therapeutic strategies to enhance anti-helminth immunity while limiting pathologic inflammation and promoting tissue healing. Our findings provide new insight into alternatively activated macrophage biology and macrophage-stromal cell interactions, which could be broadly applicable to resolving mucosal tissue injury and inflammation that are of significant public health concern.