HDAC3 inhibition stabilizes the IL-37 receptor module to enhance anti-inflammatory signaling in cystic fibrosis airway epithelium

Airway inflammation in cystic fibrosis (CF) persists despite advances in CFTR modulator therapy. IL-37b suppresses innate immune signaling through a receptor complex containing IL-18R and wild-type SIGIRR (WT-SIGIRR; IL-1R8), but this pathway is compromised in CF airway epithelial cells by the dominant-negative exon 8-skipped SIGIRR isoform ({Delta}8-SIGIRR). Here, a natural-product screen identified short-chain fatty acids as preferential enhancers of WT-SIGIRR. Pan-HDAC inhibition with panobinostat increased WT-SIGIRR, reduced {Delta}8-SIGIRR, and restored IL-37b-dependent suppression of the TLR3 ligand poly(I:C)-induced IL-8 production. Isoform-selective inhibitor screening and siRNA knockdown identified HDAC3 as a regulator of the IL-37 receptor module. Low concentrations of RGFP966 and HDAC3 silencing increased WT-SIGIRR and IL-18R protein abundance without inducing their mRNA levels. HDAC3 inhibition delayed proteasome-dependent WT-SIGIRR turnover and stabilized IL-18R, thereby enhancing IL-37b-mediated anti-inflammatory signaling in CF airway epithelial cells.