Resolving Endoplasmic Reticulum‐Protein Misfolding Restores Corticosteroid Sensitivity in Experimental Models of Severe Asthma

BACKGROUND: People with severe steroid-resistant asthma are refractory to treatment with the mainstay inhaled corticosteroids (ICS), emphasising the urgent need for alternative therapies. This study aimed to assess the effect of endoplasmic reticulum stress (ERS) on steroid responsiveness and to evaluate the efficacy of 4-phenylebuteric acid (4-PBA) as an add-on treatment to restore steroid responses in severe asthma. METHODS: The relationship between ERS and steroid response was assessed by treating human airway epithelial cells (AEC) with chemical ERS inducers or TNF, IFN-γ, and IL-17, and assessing the effects of dexamethasone (Dex) and 4-PBA. The correlation between genes associated with ERS and GR-signalling was assessed in sputum cells from patients with severe asthma, and the effects of 4-PBA were assessed in two murine models of severe, steroid-resistant asthma. RESULTS: Chemical ERS inducers significantly downregulated the expression of corticosteroid-responsive genes, HSD11B2 and FKBP5 and reduced GR nuclear translocation in basal AECs. Treatment with TNF, IFN-γ and IL-17 upregulated ERS and protein misfolded markers while reducing Dex-induced GR nuclear translocation. In sputum cells from patients with severe asthma, ERS genes negatively correlated with GR-signalling. In differentiated primary bronchial epithelial cells (pBECs), treatment with 4-PBA reversed TNF, IFN-γ and IL-17-induced steroid resistance by upregulating HSD11B2 and FKBP5 gene expression and downregulating inflammatory genes. 4-PBA together with Dex significantly reduced airway inflammation and/or AHR in experimental models of severe, steroid-resistant asthma. CONCLUSION: We provide evidence for ERS inducing steroid resistance that underpins severe asthma and demonstrate a therapeutic potential for restoring steroid sensitivity in severe asthma with 4-PBA.