IRE1α Is a Therapeutic Target for Cystic Fibrosis Airway Inflammation

Area of Science:

• Molecular Biology
• Immunology
• Cell Biology

Background:

• Cystic Fibrosis (CF) airway disease requires novel anti-inflammatory treatments.
• Endoplasmic reticulum stress transducer inositol requiring enzyme 1α (IRE1α) is implicated in CF airway inflammation.
• IRE1α activation leads to X-box binding protein-1 splicing (XBP-1s), a key factor in cytokine production.

Purpose of the Study:

• To investigate if IRE1α kinase and RNase inhibition can decrease cytokine production in CF airway epithelial cells.
• To determine if IRE1α expression and XBP-1s levels are elevated in native CF bronchial epithelia.
• To assess the efficacy of the IRE1α inhibitor KIRA6 against CF airway inflammation.

Main Methods:

• Primary cultures of homozygous F508del CF human bronchial epithelia (HBE) were exposed to supernatant of mucopurulent material (SMM).
• IRE1α expression and XBP-1s levels were evaluated in CF vs. normal HBE.
• FRET assay confirmed KIRA6 binding to IRE1α; F508del HBE were treated with SMM and KIRA6 to measure XBP-1s, IL-6, and IL-8 mRNA and protein levels.

Main Results:

• IRE1α mRNA and XBP-1s mRNA levels were significantly upregulated in CF HBE compared to normal HBE.
• SMM exposure increased XBP-1s, IL-6, and IL-8 mRNA levels and protein secretion; KIRA6 treatment dose-dependently inhibited these responses.
• Current triple CFTR modulators did not affect SMM-induced XBP-1s levels or cytokine production, even with KIRA6.

Conclusions:

• IRE1α activation is a key mediator of cytokine production in cystic fibrosis airway inflammation.
• Small molecule IRE1α kinase inhibitors, like KIRA6, show therapeutic potential by reducing RNase-dependent XBP-1s.
• Targeting the IRE1α pathway offers a promising new strategy for managing CF airway inflammation.