EP4 agonist increases myeloid derived suppressor cells activity and reduces airway inflammatory events in a murine model of asthma

Background: Previously, we showed that EP4 receptor agonist increases the number and suppressive activity of myeloid derived suppressor cells (MDSCs; both G-MDSCs and M-MDSCs) in the bone marrow culture in vitro. Methods: In the first part, mice were rendered asthmatic using HDM and then the role of intravenous adoptive transfer of MDSCEP4 (MDSCs generated and activated using the EP4 agonist in vitro) was assessed. In the second part, the role of three different doses of intravenous EP4 receptor agonist L902,688 (0.1, 0.2 and 0.4 mg/kg) on in vivo generation of MDSCs and respectively their anti-inflammatory role in asthmatic mice was studied. Results: We found that adoptive transfer of MDSCEP4 could ameliorate the immune response in a murine asthma model. Furthermore, EP4 agonist therapy increases the number of MDSCs in the spleen and lung of asthmatic mice, in a dose response manner, and reduces the inflammatory responses and histopathological changes. Furthermore, MDSCs isolated from EP4 agonist treated asthmatic mice could significantly reduce the proliferation of CD4+ T cells mainly through arginase 1 and inducible nitric oxide synthase. Conclusion: Our results demonstrate that EP4 agonist generates and activates anti-inflammatory MDSCs to suppress the proliferation of T cells and airway inflammation, likely by upregulating arginase 1 and inducible nitric oxide synthase. EP4 agonist therapy seems to be a potential therapeutic target that would ultimately result in anti-inflammatory effects in asthmatic patients through generation and activation of MDSCs.