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

前列腺素E2 （PGE2）是环氧化酶（COX）的产物，其产生受到阿司匹林等药物的抑制。PGE2具有免疫调节特性，可作为抗炎介质，特别是在气道中。一些哮喘患者在摄入阿司匹林或类似的COX抑制剂时，甚至会出现严重的哮喘反应。在我们之前的工作中，我们可以证明阿司匹林诱导的哮喘患者表现出炎症性巨噬细胞记忆。即使在体外培养一周后，这些患者的巨噬细胞对促炎触发因素（如LPS）的反应也显示出夸大的炎症介质产生。我们在HDM过敏患者的巨噬细胞中也进行了类似的观察，它们也显示出过度的炎症细胞因子和脂质介质的产生。在目前的提议中，我们现在的目的是研究PGE2是否在这种炎症性巨噬细胞记忆中起调节作用。因此，我们将研究在药物或基因抑制PGE2合成酶（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。通过小鼠模型或屋尘螨过敏性哮喘，我们将进一步研究巨噬细胞中mPGES-1或COX基因缺失对气道炎症和炎症性巨噬细胞记忆的影响。虽然PGE2在哮喘和过敏中的免疫调节作用是已知的，但它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，我们可以证明肠道寄生虫多回Heligmosomoides polygyrus bakeri （Hpb）感染导致前列腺素的产生。此外，在最近发表的一篇文章中，我们描述了Hpb产品诱导的巨噬细胞来源的PGE2对过敏性气道炎症和巨噬细胞炎症效应功能的抗炎作用。现在，我们的目标是在巨噬细胞缺乏mPGES-1或COX-2的小鼠中研究PGE2和其他COX产物在蠕虫寄生虫感染中的作用。特别是，我们的目标是通过研究蠕虫感染或hdm致敏小鼠中巨噬细胞缺乏mPGES-1或COX2的宿主防御和组织修复或过敏性气道炎症，确定巨噬细胞在2型免疫反应中产生PGE2和其他COX代谢物的作用。综上所述，我们旨在破解炎症性疾病中巨噬细胞激活和记忆的重要机制，了解PGE2及其常用药物抑制对免疫反应的影响。

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.