The role of prostaglandin E2 receptor 4 (EP4) on myeloid-derived suppressor cells in asthma exacerbation

• Applicant: Privatdozent Dr. Saeed Kolahian
• Subject Area: Clinical Immunology and Allergology ; Immunology ; Pharmacology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 519089268

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of innate immunity with remarkable suppressive functions on T-cell responses. Recently we reported that (i) adoptively transferred PMN-MDSCs inhibit Th2/Th17-dominant inflammation in asthmatic mice in vivo, (ii) PGE2 increases MDSCs generation and immunosuppressive activity through EP4 receptor in vitro, (iii) EP4 agonist L-902,688 increases the expression of Arg1 and iNOS in MDSCs in vitro, (iv) EP4 agonism alone or Arg1 administration ameliorated lung inflammatory responses and histopathological changes in asthmatic mice, (v) MDSCs act anti-inflammatory in asthma in vivo through an EP4-mediated mechanism and (vi) Influenza virus A (IAV) infection augments the increase of MDSCs number and immunosuppressive activity in a murine chronic model of HDM-induced asthma. However, the role of the EP4 receptor on MDSCs in asthma exacerbation, a mixed infection and exaggerated inflammatory condition, has not been investigated. Therefore, a detailed characterization of the role of the EP4 receptor on immunosuppressive MDSCs in asthma exacerbation is of importance. Also, the risk-benefit ratio of EP4 agonist as a new generation of bronchodilator/anti-inflammatory medication in asthma therapy needs to be elucidated. To this end, we will study the role of the EP4 receptor on MDSCs in a mixed allergic-infective setting in the HDM model of IAV-induced asthma exacerbation. Our study will not only focus on the early stage of allergic airway inflammation mainly driven by eosinophils but also on the post-allergic airway inflammatory condition (after clearance of the eosinophilic inflammation) to compare the latent ongoing inflammation to the obvious eosinophilic feature of allergic airway inflammation in a murine HDM model of IAV-induced asthma exacerbation. Furthermore, the role of EP4 receptor on the host immune defense against influenza virus infection will be investigated. Therefore, we aim to perform the following studies to investigate: (i) the impact of EP4 agonist L-902,688 on the generation and activation of MDSCs and distinct subset of T cells in a HDM model of IAV-induced asthma exacerbation, (ii) downstream pathway(s) of the EP4 receptor on Arg1 production in MDSCs, and (iii) the anti-inflammatory effect of the pharmacologic intervention with Arg1 (BCT-100) in a HDM model of IAV-induced asthma exacerbation. This study could pave the way for the development of a new treatment strategy for chronically stable asthma and its life-threatening complication, asthma exacerbation.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Harald Renz