Prostaglandin E2 as a regulator of host defense, repair and macrophage reprogramming in type-2 immunity

前列腺素E2（PGE 2）是环氧合酶（考克斯）的产物，其产生被药物如阿司匹林抑制。PGE 2具有免疫调节特性，可以作为抗炎介质，特别是在气道中。一些哮喘患者在摄入阿司匹林或类似的考克斯抑制剂时甚至会出现严重的哮喘反应。在我们以前的工作中，我们可以证明阿司匹林诱导的哮喘患者表现出炎症巨噬细胞记忆。即使在体外培养一周后，来自这些患者的巨噬细胞也显示出响应于促炎触发物如LPS的过度的炎性介质产生。我们在HDM过敏患者的巨噬细胞中进行了类似的观察，也显示出过度的炎症细胞因子和脂质介质产生。在本提案中，我们现在的目标是调查是否PGE 2在这种炎症巨噬细胞记忆中发挥调节作用。因此，我们将研究在药理学或遗传学抑制PGE 2合酶（mPGES-1）后，人巨噬细胞（来自健康个体或哮喘患者）中促炎介质（脂质介质、细胞因子、趋化因子）的产生。我们将进一步研究巨噬细胞中mPGES-1或考克斯基因缺失对气道炎症和炎症巨噬细胞记忆的影响。虽然PGE 2在哮喘和过敏中的免疫调节作用是已知的，但其在蠕虫寄生虫感染中的作用尚不清楚。在我们的初步工作中，我们可以表明，感染肠道寄生虫Heligmosomoides polygyrus bakeri（Hpb）的结果，在生产的三尖杉酯碱。此外，在最近的出版物中，我们已经描述了巨噬细胞衍生的PGE 2的抗炎作用，诱导过敏性气道炎症和巨噬细胞的炎症效应功能的幽门螺杆菌产品。现在，我们的目标是研究PGE 2和其他考克斯产品在蠕虫寄生虫感染小鼠缺乏mPGES-1或考克斯-2在巨噬细胞中的作用。特别是，我们的目标是确定的作用，巨噬细胞在生产的PGE 2和其他考克斯代谢产物在2型免疫反应中，通过研究宿主防御和组织修复或过敏性气道炎症蠕虫感染或HDM致敏的小鼠，缺乏mPGES-1或COX 2的巨噬细胞。总之，我们的目标是破译炎症性疾病中巨噬细胞活化和记忆的重要机制，以及了解PGE 2及其常用药物对免疫反应的抑制作用。

Prostaglandin E2 (PGE2) is a product of the enzyme cyclooxygenase (COX), the production of which is inhibited by drugs such as Aspirin. PGE2 has immune regulatory properties und can act as an anti-inflammatory mediator, particularly in the airways. Some asthma patients even experience severe asthmatic reactions, when they ingest aspirin or similar COX inhibitors. In our previous work, we could show that patients with aspirin-induced asthma exhibit an inflammatory macrophage memory. Even after one week of in vitro culture, macrophages from these patients show exaggerated inflammatory mediator production in response to pro-inflammatory triggers such as LPS. We made similar observations in macrophages from HDM allergic patients, which also showed exaggerated inflammatory cytokine and lipid mediator production. In the present proposal we now aim to investigate whether PGE2 plays a regulatory role in this inflammatory macrophage memory. Thus, we will investigate the production of pro-inflammatory mediators (lipid mediators, cytokines, chemokines) in human macrophages (from healthy individuals or asthma patients), after pharmacological or genetic inhibition of PGE2 Synthase (mPGES-1). Using a mouse mode or house dust mite allergic asthma, we will further investigate the effect of genetic deletion of mPGES-1 or COX in macrophages on airway inflammation and on the inflammatory macrophage memory.While the immune regulatory role of PGE2 in asthma and allergy is known, its role in infections with worm parasites is less clear. In our preliminary work, we could show that infection with the intestinal parasite Heligmosomoides polygyrus bakeri (Hpb) results in the production of prostaglandins. In addition, in a recent publication, we have described an anti-inflammatory effect of macrophage-derived PGE2, induced by Hpb products on allergic airway inflammation and on inflammatory effector functions of macrophages. Now, we aim to investigate the role of PGE2 and other COX products during worm parasite infection in mice lacking mPGES-1 or COX-2 in macrophages. In particular, we aim to identify the role of macrophages in the production of PGE2 and other COX metabolites during type 2 immune responses by studying host defense and tissue repair or allergic airway inflammation in helminth-infected or HDM-sensitized mice that lack mPGES-1 or COX2 in macrophages. In summary, we aim to decipher important mechanisms of macrophage activation and memory in inflammatory disease as well as to understand the effects of PGE2 and its inhibition by commonly used drugs on immune responses.