Work

Pharmacological inhibition of RNA-binding protein HuR by KH-3 attenuates GATA3-driven Th2 cytokine expression and airway inflammation in allergic asthma 3932

Year: 2025

Type: article

Abstract: Description Allergic asthma remains difficult to treat despite biologics targeting specific Th2-related mediators. Inhibiting the RNA-binding protein HuR (ELAVL1), a key regulator of these markers, offers a promising therapeutic strategy. We previously showed that HuR regulates GATA3 and Th2 cytokine expression by modulating their mRNA stability, making HuR a potential therapeutic target. Here, we evaluated KH-3, a potent small-molecule HuR inhibitor, for its ability to modulate Th2-driven inflammation in a house dust mite (HDM)-induced allergic airway inflammation model. KH-3 treatment reduced airway inflammation and Th2 cytokine levels (IL-4, IL-5, IL-13) in the lungs, measured by ELISA of bronchoalveolar lavage fluid (BALF) and lung homogenates, aligning with qPCR data from lung homogenates. qPCR data also showed significant reduction in GATA3 expression in KH-3-treated mice. In vitro, KH-3-pretreated splenic CD4+ T cells from control mice showed reduced Th2 cytokine and GATA3 expression upon activation. To investigate HuR’s role in GATA3-driven Th2 cytokine production, we developed a novel transgenic mouse model with inactivated GATA3-HuR binding sites (CD4-Cre ROSA-GATA3 knock-in). Activated splenic CD4+ cells from these mice showed significantly reduced Th2 cytokine levels, similar to KH-3-treated splenic CD4+ cells control mice. These findings highlight KH-3’s potential as a novel strategy to disrupt GATA3-driven Th2 responses and mitigate airway inflammation in allergic asthma. Funding Sources Supported by VA Merit grant: CX002491; and NIH: R21-AI-173487-01. Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.1674

Authors: Laura Vallance, Fatemeh Fattahi, Julia Holden, Brandon Tepper, Kareem Hussein, Ulus Atasoy

Institution: University of Michigan

Language: English

Topic: Asthma and respiratory diseases

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,500