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

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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.