Defective Gene Activates Inflammation Associated with Cystic Fibrosis

Cystic fibrosis (CF) is a genetic lung disease marked by chronic and excessive lung inflammation, mucus retention, and airway obstruction due to recurrent bacterial and viral infections. While it has been known for some time that increased cytokine interleukin-8 (IL-8) production results in hyperinflammation like that seen in CF, the exact underlying mechanisms remain debatable. A research team from Japan decided to investigate these mechanisms using molecular techniques on lung epithelial cells of patients with CF.

Their work, published in the International Journal of Molecular Sciences, examined a membrane protein known as single immunoglobulin interleukin-1 receptor (IL-1R)-related molecule (SIGIRR). SIGIRR is a negative regulator of TLRs, or "toll-like receptor" genes that cause inflammation in epithelial cells in response to pathogen-associated molecular patterns, or PAMPS. These immune signals are responsible for alerting cells of infection. Pathways that negatively regulate TLRs, such as SIGIRR, can induce inflammatory disruptions of viral infections. 

The team's findings suggested that the cell surface expression of SIGIRR was much lower in sampled CF epithelial cells compared to non-CF epithelial cells. Surprisingly, they also observed high expression of an alternative, spliced isoform of SIGIRR in CF epithelial cells, known as ∆8-SIGIRR.

"We discovered that ∆8-SIGIRR is formed due to dysfunctional mRNA splicing, which leads to the loss of a DNA segment known as exon-8 from the full-length SIGIRR, known as WT-SIGIRR," says Associate Professor Tsuyoshi Shuto from Graduate School of Pharmaceutical Sciences at Kumamoto University, Japan.

Upon further investigation, the researchers discovered that increased expression of ∆8-SIGIRR on the cell membrane of CF lung epithelial cells decreased the expression and functionality of WT-SIGIRR, making IL-37b, an anti-inflammatory molecule inhibiting TLRs, inactivation impossible. This could be another molecular mechanism contributing to CF's severe inflammation in tissues.

"Our findings will lead to a deeper understanding of the pathological function of ∆8-SIGIRR in CF. Naturally, this will pave the way for the development of novel SIGIRR-targeting drugs for previously unknown targets of CF-associated inflammation," says Professor Shuto.

IL37-SIGIRR's defective signaling, resulting in persistent activation of inflammatory TLRs, is a novel discovery into the mechanisms underlying CF-associated inflammation. In the future, the team can further investigate which drugs can effectively target these new receptors and analyze the impacts on CF-associated inflammation.