RELM-alpha regulation of hookworm-induced lung inflammation

描述（由申请方提供）：蠕虫感染引起辅助性T细胞2型（Th 2）反应，这对保护性免疫至关重要。虽然Th 2细胞在限制寄生虫负荷方面发挥着重要作用，但这些相同的反应也会引起慢性蠕虫诱导的炎症。此外，Th 2细胞因子应答也参与与过敏、哮喘和慢性阻塞性肺病（COPD）相关的有害炎症。因此，更好地了解Th 2细胞反应是如何调节的，可以提供新的机会来设计治疗方法，以促进抗寄生虫免疫和限制Th 2细胞相关的炎症性疾病。分泌的蛋白质HSP 7 Ma最近被鉴定为一种有效的免疫调节分子，可以在多种蠕虫感染模型中限制炎症。在这个建议中，我们将采用钩虫感染诱导的肺部炎症模型来描述如何调节HLA-Ma表达，并确定HLA-Ma介导的肺部炎症抑制的下游靶点。我们的初步数据表明，感染日本圆线虫巴西（Nb）促进慢性肺部炎症，这是与上皮细胞，交替激活的巨噬细胞和嗜酸性粒细胞的表达。此外，IgM缺陷（Retnla-/-）小鼠表现出恶化的慢性肺部炎症，以及增加的巨噬细胞和Th 2细胞因子应答。然而，促进HPLIMA表达的因素和HPLIMA介导的组织保护的细胞谱系限制的要求是未知的。此外，在Retnla-/-小鼠中介导加重的肺部炎症的下游因子和细胞类型是不确定的。在目标1中，将采用细胞特异性缺失、骨髓嵌合体和细胞转移的组合方法来鉴定促进BCLMa表达的细胞类型和细胞衍生因子，以及BCLMa限制Nb诱导的慢性肺部炎症的机制。了解是什么调控了HLA-Ma的表达，以及HLA-Ma如何介导组织保护，可以为利用HLA-Ma的生物学功能治疗或预防肺部炎症提供新的机会。在我们的初步数据调查如何Nb诱导的肺中的CD 45 Ma表达开始，一个以前未被认识的途径的巨噬细胞-嗜碱性粒细胞交叉调节被发现，其中嗜碱性粒细胞诱导巨噬细胞募集和CD 45 Ma的表达。此外，Pneumoma提供负反馈调节以限制嗜碱性粒细胞功能。基于这些发现，目的2将采用Nb感染和肺嗜碱性粒细胞增多的体内模型来研究嗜碱性粒细胞如何介导巨噬细胞活化和巨噬细胞的表达。最后，一种新的巨噬细胞-嗜碱性粒细胞共培养系统将被用来描绘嗜碱性粒细胞-巨噬细胞交叉调节的分子机制。鉴于嗜碱性粒细胞作为Th 2细胞因子应答中关键的先天性细胞的出现，研究嗜碱性粒细胞：巨噬细胞相互作用如何调节可以增加我们对如何操纵Th 2细胞因子依赖性免疫和炎症的理解。 公共卫生相关性：土壤传播的蠕虫寄生虫感染估计有20亿人，代表了一个重大的全球公共卫生问题。虽然抗寄生虫免疫应答的某些方面对于减少寄生虫负担是至关重要的，但也已知它们有助于慢性蠕虫诱导的疾病以及与过敏、哮喘和慢性阻塞性肺病相关的有害炎症。在这项提案中，我们将描述分泌蛋白P16 Ma在限制蠕虫诱导的过度肺部炎症中的作用，并预测我们的研究结果将增加我们对如何治疗与感染，哮喘或过敏相关的慢性肺部炎症的理解。

DESCRIPTION (provided by applicant): Helminth infections provoke a T helper type 2 (Th2) cell response, which is critical for protective immunity. Although it is clear that Th2 cells play an essential role in limiting parasite burden, these same responses also cause chronic helminth-induced inflammation. Moreover, Th2 cytokine responses are also involved in the detrimental inflammation associated with allergy, asthma and chronic obstructive pulmonary disease (COPD). Therefore, a better understanding of how Th2 cell responses are regulated could offer new opportunities to design treatments both to promote anti-parasite immunity and limit Th2 cytokine-associated inflammatory disorders. The secreted protein RELMa was recently identified as a potent immuno-regulatory molecule that could limit inflammation in multiple helminth infection models. In this proposal, we will employ a model of hookworm infection-induced lung inflammation to delineate how RELMa expression is regulated, and to determine the downstream targets of RELMa-mediated inhibition of lung inflammation. Our preliminary data demonstrate that infection with Nippostrongylus brasiliensis (Nb) promotes chronic lung inflammation that is associated with RELMa expression by epithelial cells, alternatively activated macrophages and eosinophils. Further, RELMa-deficient (Retnla-/-) mice exhibited exacerbated chronic lung inflammation, and increased macrophage and Th2 cytokine responses. However, the factors that promote RELMa expression and the cell lineage-restricted requirements for RELMa-mediated tissue protection are unknown. Additionally, the downstream factors and cell-types mediating exacerbated lung inflammation in Retnla-/- mice are undefined. In Aim 1, the combined approaches of cell-specific deletions, bone marrow chimeras and cell transfers will be employed to identify the cell types and cell-derived factors that promote RELMa expression, and the mechanism through which RELMa limits Nb-induced chronic lung inflammation. Knowledge of what regulates RELMa expression, and how RELMa mediates tissue protection, could provide new opportunities to harness the biologic function of RELMa for therapies to treat or prevent lung inflammation. In our preliminary data investigating how Nb-induced RELMa expression in the lung is initiated, a previously unrecognized pathway of macrophage-basophil cross-regulation was uncovered, in which basophils induce macrophage recruitment and expression of RELMa. Further, RELMa provides a negative feedback regulation to limit basophil function. Based on these findings, Aim 2 will employ both Nb infection and an in vivo model of lung basophilia to examine how basophils mediate macrophage activation and expression of RELMa. Finally, a novel macrophage-basophil co-culture system will be employed to delineate the molecular mechanisms of basophil-macrophage cross-regulation. Given the emergence of basophils as critical innate cells in Th2 cytokine responses, investigating how basophil:macrophage interactions are regulated could increase our understanding of how to manipulate Th2 cytokine-dependent immunity and inflammation. PUBLIC HEALTH RELEVANCE: Soil transmitted helminth parasites infect an estimated two billion people and represent a significant global public health problem. While certain aspects of the anti-parasite immune response are critical for reducing parasite burden, they are also known to contribute to chronic helminth-induced disease as well as to the detrimental inflammation associated with allergy, asthma and chronic obstructive pulmonary disease. In this proposal, we will delineate the role of the secreted protein RELMa in limiting excessive helminth-induced lung inflammation, and predict that our findings will increase our understanding of how to treat chronic lung inflammation associated with infection, asthma or allergy.