RELM-alpha regulation of hookworm-induced lung inflammation

描述(申请人提供)：蠕虫感染引发T型辅助者2型(Th2)细胞反应，这对保护性免疫至关重要。虽然很明显Th2细胞在限制寄生虫负担方面发挥了重要作用，但这些相同的反应也会引起慢性蠕虫引起的炎症。此外，Th2细胞因子反应也参与了与过敏、哮喘和慢性阻塞性肺疾病(COPD)相关的有害炎症。因此，更好地了解Th2细胞反应是如何调节的，可以为设计治疗方案提供新的机会，既可以促进抗寄生虫免疫，又可以限制Th2细胞因子相关的炎症疾病。分泌蛋白RELMa最近被确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。在这个方案中，我们将使用钩虫感染诱导的肺部炎症模型来描述RELMa的表达是如何调节的，并确定RELMa介导的抑制肺部炎症的下游靶点。我们的初步数据表明，感染巴西拟青霉可促进慢性肺部炎症，这与上皮细胞、激活的巨噬细胞和嗜酸性粒细胞表达RELMa有关。此外，RELMA缺陷(Retnla-/-)小鼠表现出慢性肺部炎症加重，巨噬细胞和Th2细胞因子反应增强。然而，促进RELMa表达的因素以及对RELMa介导的组织保护的细胞谱系限制要求尚不清楚。此外，介导Retnla-/-小鼠肺部炎症加重的下游因素和细胞类型尚不清楚。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相结合的方法来鉴定促进RELMa表达的细胞类型和细胞衍生因子，以及RELMa抑制NB诱导的慢性肺炎症的机制。了解是什么调控RELMa的表达，以及RELMa如何介导组织保护，可以为治疗或预防肺部炎症提供新的机会来利用RELMa的生物功能。在我们的初步数据中，研究了NB诱导的RELMa在肺中的表达是如何启动的，发现了一条先前未知的巨噬细胞-嗜碱性粒细胞相互调节的途径，在该途径中，嗜碱性粒细胞诱导巨噬细胞募集和表达RELMa。此外，RELMa提供负反馈调节来限制嗜碱性细胞的功能。基于这些发现，AIM 2将同时使用NB感染和肺嗜碱性粒细胞体内模型来研究嗜碱性粒细胞如何介导巨噬细胞激活和RELMa的表达。最后，一个新的巨噬细胞-嗜碱性细胞共培养系统将被用来描绘嗜碱性细胞-巨噬细胞交叉调节的分子机制。鉴于嗜碱性粒细胞作为Th2细胞因子反应中的关键先天细胞的出现，研究嗜碱性粒细胞与巨噬细胞的相互作用是如何调节的，可以增加我们对如何操纵Th2细胞因子依赖的免疫和炎症的理解。

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.