Contribution of Protein Arginine Methyltransferase (PRMT)5 to House Dust Mite Asthma

Abstract

Abstract Severe asthma affects 2.4 million Americans and 23.8 million people worldwide and accounts for the majority of total asthma hospital costs. Most severe asthma is mediated by Th17/neutrophilic responses, alone or combined with Th2 and/or Th1 responses. In contrast, Treg responses are deficient. Protein Arginine Methyl Transferase (PRMT) 5 catalyzes symmetric dimethylation (SDM) of arginine on histones and other proteins, thereby regulating gene expression. PRMT5 promotes murine Th1/Th17 responses in central nervous system autoimmunity. However, its impact on asthma has not been established. We evaluated the role of PRMT5 on mouse models of house dust mite (HDM) asthma. PRMT5 and its symmetric demethylation activity were increased in lung infiltrating cells during Th2/Th17-mediated HDM severe asthma, suggesting a role for PRMT5 in asthma pathogenesis. To determine the contribution of PRMT5 to HDM asthma pathogenesis, we used first-in-class PRMT5-specific inhibitors developed at The Ohio State University. PRMT5 inhibitor HLCL65 modulated Th1, Th2 and Th17 differentiation and suppressed airway hyperreactivity in Th2/Th17 models of house dust mite (HDM)-induced asthma. Overall, these results support a role for PRMT5 in severe asthma pathogenesis.