Myeloid-Derived Suppressor Cells Dampen Airway Inflammation Through Prostaglandin E2 Receptor 4

Abstract

Emerging evidence suggests a mechanistic role for myeloid-derived suppressor cells (MDSCs) in lung diseases like asthma. Previously, we showed that adoptive transfer of MDSCs dampens lung inflammation in murine models of asthma through cyclooxygenase-2 and arginase-1 pathways. Here, we further dissected this mechanism by studying the role and therapeutic relevance of the downstream mediator prostaglandin E2 receptor 4 (EP4) in a murine model of asthma. We adoptively transferred MDSCs generated using an EP4 agonist in a murine model of asthma and studied the consequences on airway inflammation. Furthermore, pegylated human arginase-1 was used to model MDSC effector activities. We demonstrate that the selective EP4 agonist L-902,688 increased the number and suppressive activity of MDSCs through arginase-1 and nitric oxide synthase-2. These results showed that adoptive transfer of EP4-primed MDSCs, EP4 agonism alone or arginase-1 administration ameliorated lung inflammatory responses and histopathological changes in asthmatic mice. Collectively, our results provide evidence that MDSCs dampen airway inflammation in murine asthma through a mechanism involving EP4.

Immune Metabolism–An Opportunity to Better Understand Allergic Pathology and Improve Treatment of Allergic Diseases?

“…These controversial studies show, that more detailed analyses are required. A recent study in 2021 by Geffen et al ( 79 ) demonstrated that prostaglandin E2 receptor 4 (EP4) agonist-primed MDSCs increased arginase-1- and nitric oxide synthase-2 production. Besides, the treatment with the EP4 agonist increased immunosuppressive activity of MDSCs on T cell responses in asthmatic mice ( 79 ).…”

“…A recent study in 2021 by Geffen et al ( 79 ) demonstrated that prostaglandin E2 receptor 4 (EP4) agonist-primed MDSCs increased arginase-1- and nitric oxide synthase-2 production. Besides, the treatment with the EP4 agonist increased immunosuppressive activity of MDSCs on T cell responses in asthmatic mice ( 79 ). As prostaglandin E2 is one of the intermediates that occur during a disrupted Krebs cycle, the investigated increase of arginase-1/nitric oxide synthase-2 can probably be attributed to changes in cellular metabolism.…”

Pharmacological modulation of myeloid-derived suppressor cells to dampen inflammation

“…MDSC cell therapy may be another promising strategy in this list, especially considering its potent immunosuppressive capacity and its role in maintaining immune tolerance in transplantation and autoimmunity. Several pre-clinical studies have shown promising therapeutic effects of the adoptive transfer of MDSCs in organ transplantation, autoimmune diseases as well as in a variety of other immune-related disorders, such as cyclosporin A-induced hypertension, heart failure and asthma ( 63 , 69 , 93 – 100 ). Here, we briefly discuss some of the cytokines and pharmacological compounds that have been identified to promote the generation and/or activation of MDSCs in vitro / ex vivo and were applied as MDSC cell therapy.…”

“…PGE 2 , in combination with GM-CSF and either IL-4 or IL-6, was found to efficiently induce MDSCs ex vivo ( 55 , 100 ). From the four EP subreceptors (EP1-4) of PGE 2 , EP2 and EP4, and not EP1 and EP3, were found to induce MDSC development, hinting at an important role of the adenylate cyclase/cAMP/PKA/CREB signaling pathway ( 55 , 100 ).…”

“…PGE 2 , in combination with GM-CSF and either IL-4 or IL-6, was found to efficiently induce MDSCs ex vivo ( 55 , 100 ). From the four EP subreceptors (EP1-4) of PGE 2 , EP2 and EP4, and not EP1 and EP3, were found to induce MDSC development, hinting at an important role of the adenylate cyclase/cAMP/PKA/CREB signaling pathway ( 55 , 100 ). Furthermore, the adoptive transfer of MDSCs generated in the presence of a selective EP4 receptor agonist dampened airway inflammatory features in a murine model of asthma ( 100 ).…”