Associate Professor, Internal Medicine, Division Chief, Allergy Immunology, Ann Arbor VA

RNA binding protein HuR posttranscriptionally regulates CD4+ T cell inflammatory gene expression in asthma
Ulus Atasoy1, Fatemeh Fattahi1, Jason Ellis1, Kristin Bahleda1, Nerissa Reister1, Njira Lugogo1,
1 University of Michigan, Ann Arbor, MI.

Due to poor correlation between steady-state mRNA levels and protein product, transcriptomic analyses may miss critical genes controlling inflammation. Many genes are regulated posttranscriptionally at levels of mRNA stability and translation by RNA-binding proteins (RBPs) and miRNAs, however this is not well understood. Pro-inflammatory genes which play pivotal roles in airway inflammation usually have labile mRNA transcripts and are regulated posttranscriptionally. Using novel RIP-Seq methods, we have uncovered how RBP HuR (elavl1) regulates key genes involved in CD4+ Th subset differentiation since it binds to and regulates gata3 and Th2 cytokine mRNAs. HuR regulates inflammatory genes allowing for lung inflammation in asthma. We previously demonstrated that HuR overexpression in CD4+ T cells results in increases in Th2 cytokine production. Conditional ablation of HuR in T cells (distal Lck-cre HuRfl/fl), abrogates Th2 differentiation, cytokine production and lung inflammation in ova challenge model. We hypothesized that HuR may similarly regulate lung inflammation in human asthma. We discovered that HuR protein expression is greatly increased (100%) in peripheral CD4+ T cells from asthmatics (both type 2 high and low) compared with healthy individuals. Asthmatic PBLs have increased frequency and production of both Th2/Th17 signature cytokines. Using a drug (acadesine aka AICAR) which interferes with HuR function, we show that CD4+ T cells treated with acadesine have decreases in Th2/17 cytokine expression. Taken together, these data suggest that HuR plays a permissive role in both allergen and non-allergen driven airway inflammation by regulating key genes and that interfering with its function may be a novel way to treat asthma.