Cystic fibrosis (CF) is typically characterized by infection-associated airway epithelial inflammation. Here, we showed that cell surface expression of SIGIRR/TIR8, an immunoglobulin-like membrane protein that is essential for negative regulation of toll-like receptors (TLRs)-associated inflammatory signals, is specifically and remarkably decreased in CF and CF-like airway epithelial cells. These CF-associated cells specifically and highly expressed a unique, alternative splice isoform of SIGIRR that lacks exon 8 (Δ8-SIGIRR),
which contributes to the suppression of functional SIGIRR plasma membrane expression. Consistently, a SIGIRR ligand IL-37b failed to suppress inflammatory signals induced by poly(I:C), a synthetic analog of viral RNA. Finally, poly(I:C)-dependent anti-inflammatory IL-37b secretion was also significantly decreased in CF cells, suggesting the dysregulation of anti-inflammatory receptor SIGIRR as well as its ligand IL-37b in CF cells. Thus, our studies demonstrate that poly(I:C)-dependent anti-inflammatory feedback loop, or IL-37b-SIGIRR negative feedback signal, is defective in CF airway epithelial cells due to unique splicing switch of SIGIRR gene.