Systemic EP4 receptor agonist and Arginase-1 therapy in a murine model of chronic asthma and influenza virus-induced asthma exacerbation

Background and Purpose Myeloid-derived suppressor cells (MDSCs) play important roles in the pathogenesis of asthma. Recent studies demonstrate that their function can be modulated by different pharmacological approaches. In this study, we focused on the effects of systemically administered prostaglandin EP4 receptor agonist L-902,688 and pegylated human Arginase-1 on MDSCs in a murine model of chronic asthma and asthma exacerbation. Experimental Approach BALB/c mice were challenged with house dust mite (HDM) over a period of 5 weeks, establishing a chronic asthma phenotype. To induce asthma exacerbation, mice were infected with Influenza Virus H1N1 A/Puerto Rico/8/1934. In vivo lung function, lung inflammatory features, number and suppressive activity of MDSCs, number of different T cell subsets in lung and spleen and viral titer in the bronchoalveolar lavage fluid (BALF) were assessed. Key Results In asthmatic mice, treatment with the EP4 receptor agonist or Arginase-1 significantly reduced the number of eosinophils in the BALF. Both treatments improved lung function and ameliorated airway hyperresponsiveness (AHR) in asthma exacerbation. The number and suppressive activity of MDSCs in the lung were increased by virus-induced asthma exacerbation. Conclusion and Implications We found beneficial effects of systemic EP4 receptor agonist and Arginase-1 therapy in a murine model of chronic asthma and influenza virus-induced asthma exacerbation. Our findings highlight the potential efficacy of EP4 receptor agonists, Arginase-1, and MDSCs, as novel therapeutic approaches in asthma and asthma exacerbation.