A critical role for the RNA binding protein HuR in CD4+ T cell-mediated airway inflammation in mouse and human

Abstract

Abstract The RNA-binding protein HuR (elavl1) positively regulates the expression of its targets by increasing mRNA stability and translation. Th2 and Th17 related genes play critical roles in airway inflammation in both mouse and human. Using in vitro and in vivo studies, we have previously shown that these proinflammatory genes are regulated by HuR. Here, we generated a conditional ablation of HuR in T cells (distal Lck-cre HuRfl/fl). We found significant decreases in Th2 differentiation, cytokine production, and lung inflammation in an alum-emulsified ovalbumin (ova-alum) model of allergic airway inflammation using this novel mouse model. We hypothesized that HuR might similarly regulate lung inflammation in human asthma. Using peripheral CD4+ T cells from 45 asthmatic patients, we found the inhibitory effect of the HuR-specific inhibitor CMLD-2, as well as an AMPK activator (acadesine aka AICAR), on both Th2/Th17 signature cytokines in both protein and mRNA levels. Our asthmatics were classified into type 2 high or non-type 2 high based on their blood eosinophil and FeNO levels. Interestingly, there were significant positive correlations between Th2 cytokine levels in CD4+ cells with levels of eosinophils and FeNO from asthmatics. Surprisingly, IFNγ (protein and mRNA) were also markedly decreased by HuR inhibition. Our bioinformatic studies also revealed proteins with high interaction with HuR including MAPK14/p38α and PTEN, common in the pathways with IFNγ, are affected by HuR inhibitor. Taken together, our mouse and human data suggest that HuR plays a crucial permissive role in both allergen- and nonallergen-driven airway inflammation by regulating key genes and that interfering with its function may be a novel way to treat asthma. Supported by R01: AI080870, R21: AI079341