Airway Surface Liquid and Impaired Antiviral Defense in Cystic Fibrosis

Voynow, Judith A.; Zheng, Shuo

doi:10.1165/rcmb.2019-0239ed

Cited by 2 publications

(1 citation statement)

References 16 publications

(23 reference statements)

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“…Many studies have demonstrated the increased activation of TLR2, TLR4, and TLR5 in CF airway epithelial cells and macrophages, which contributes to a hyperinflammatory response toward bacterial peptidoglycan (PGN), lipopeptides, lipopolysaccharide (LPS), and flagellin from Staphylococcus aureus and Pseudomonas aeruginosa that are important pathogens in pulmonary infections in CF [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Additionally, infections with respiratory viruses, including rhinovirus and influenza A and B, are strongly associated with pulmonary exacerbations due to a deficient anti-viral activity in the CF airway surface liquid (ASL), leading to increased viral replication and cytokine production via TLR3 [ 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

A Splice Switch in SIGIRR Causes a Defect of IL-37-Dependent Anti-Inflammatory Activity in Cystic Fibrosis Airway Epithelial Cells

Ueno-Shuto

Kamei

Hayashi

et al. 2022

IJMS

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Cystic fibrosis (CF) is a hereditary disease typically characterized by infection-associated chronic lung inflammation. The persistent activation of toll-like receptor (TLR) signals is considered one of the mechanisms for the CF hyperinflammatory phenotype; however, how negative regulatory signals of TLRs associate with CF inflammation is still elusive. Here, we showed that the cell surface expression of a single immunoglobulin interleukin-1 receptor (IL-1R)-related molecule (SIGIRR), a membrane protein essential for suppressing TLRs- and IL-1R-dependent signals, was remarkably decreased in CF airway epithelial cells compared to non-CF cells. Notably, CF airway epithelial cells specifically and highly expressed a unique, alternative splice isoform of the SIGIRR that lacks exon 8 (Δ8-SIGIRR), which results in the production of a C-terminal truncated form of the SIGIRR. Δ8-SIGIRR was expressed intracellularly, and its over-expression abolished the cell surface expression and function of the full-length SIGIRR (WT-SIGIRR), indicating its dominant-negative effect leading to the deficiency of anti-inflammatory activity in CF cells. Consistently, IL-37, a ligand for the SIGIRR, failed to suppress viral dsRNA analogue poly(I:C)-dependent JNK activation and IL-8 production, confirming the reduction in the functional WT-SIGIRR expression in the CF cells. Together, our studies reveal that SIGIRR-dependent anti-inflammatory activity is defective in CF airway epithelial cells due to the unique splicing switch of the SIGIRR gene and provides the first evidence of IL-37-SIGIRR signaling as a target of CF airway inflammation.

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