Posttranscriptional control of allergic airway inflammation by HuR (IRM11P.638)

Abstract

Abstract RNA binding protein HuR regulates Th2 differentiation by controlling mRNA stability of IL-4, IL-13 and GATA-3. We hypothesized HuR is required for initiation of allergic airway inflammation. We generated a distal lck-Cre ROSA HuRfl/fl mouse model to conditionally ablate HuR prior to T cell activation. HuR KO mice had 50% knockdown efficiency of YFP+ CD4+ T cells. We used ova challenge model of airway inflammation to ascertain effects of HuR KO in T cells. YFP+ HuR KO T cells migrated normally to lungs during ova challenge and had significant reductions in BAL IL-13, cellular inflammation and serum IgE. Additionally, they had completely abolished lung cellular inflammation to levels similar to non-immunized mice. We conducted in vitro activation experiments to determine mechanisms of suppression of airway inflammation. HuR KO CD4+ T cells were sorted into YFP+ (HuR lo) and YFP- (HuR WT) pools and activated. YFP+ T cells had profound decreases in IL-4, IL-5, IL-13 but not IFNλ at mRNA and protein levels. Gata-3 and IL-4 transcription were significantly reduced, as was expression of IL-2Ra (CD25). YFP+ KO T cells have reductions in p-stat5 signaling which is required for robust Th2 differentiation by activation of the IL-4 gene locus. Remarkably, though only 50% of CD4+ T cells have ablated HuR, this was sufficient to completely suppress Th2 differentiation in airway inflammation. These data reveal a pivotal role for HuR in controlling Th2 cytokines and airway inflammation.