HuR Regulates GATA3-Driven Type 2 Inflammation in CD4⁺ T cells and ILC2 in Airway Inflammation

Type 2 high asthma is driven by coordinated GATA3 dependent programs in CD4+ T cells and group 2 innate lymphoid cells (ILC2). Although biologics targeting IL4, IL5, or IL13 benefit subsets of patients, many remain symptomatic, suggesting that upstream regulatory mechanisms may sustain type 2 inflammation. We investigated whether HuR (ELAVL1), an RNA-binding protein that stabilizes GATA3 and Th2 cytokines mRNA, regulates type 2 inflammatory programs in allergic asthma. Using a house dust mite (HDM) model in vivo, HuR inhibition with the small molecule KH3 reduced lung inflammation, suppressed Th2 cytokine expression, accelerated Gata3 mRNA decay in lung CD4+ T cells, and attenuated airway hyperresponsiveness toward control levels. In ex vivo activated human lung CD4+ T cells, KH3 accelerated GATA3 mRNA decay with minimal effects on RORC or TBX21 and selectively reduced Th2 cytokine secretion, while IL10 and IL2 were unchanged. Similarly, ILC2s isolated from peripheral blood mononuclear cells (PBMCs) of type 2 high asthmatic donors showed reduced GATA3 mRNA stability and diminished Th2 cytokine production following KH3 treatment. Single-cell transcriptomic analysis of bronchoalveolar lavage fluid after allergen challenge demonstrated co-enrichment of ELAVL1 and GATA3 within Th2 clusters in human airways. Together, these findings identify HuR as a post-transcriptional regulator of GATA3 driven type 2 inflammation in allergic asthma.