Cystic fibrosis (CF) is an inherited lung disease characterized by chronic, excessive pneumonia, mucus retention and airway obstruction due to recurrent bacterial and viral infections. It is widely distributed in the population of Europe and North America.
Although it is known that increased production of interleukin-8 (IL-8) – a type of cytokine, and defects in the causative gene cause the excessive inflammation associated with cystic fibrosis, evidence suggests that some dysregulated genes also play a major role in the underlying mechanism behind her. This inflammation.
One such group of genes is the toll-like receptors (TLRs), which cause inflammation in airway epithelial cells in response to pathogen-associated molecular patterns (PAMPs) – immune signals that alert cells to infection. In many inflammatory diseases, pathways that negatively regulate TLRs, that is, prevent them from causing an inflammatory effect, are dysregulated. However, little is known about the negative regulators of TLRs that lead to inflammation in cystic fibrosis.
To address this gap, a research team led by Associate Professor Tsuyoshi Shuto from the Graduate School of Pharmaceutical Sciences at Kumamoto University, Japan and Lecturer Keiko Shuto from the School of Pharmaceutical Sciences at Sogo University, Japan, conducted a study to investigate the mechanisms underlying cystic fibrosis, by studying a membrane protein known as a molecule. Binds to the immunoglobulin interleukin-1 receptor (IL-1R) (SIGIRR). SIGIRR is known to cause inflammation by disrupting inflammatory regulation in viral infection and is a negative regulator of TLRs.
In their study published in Volume 23, Number 14 of International Journal of Molecular Sciences On July 13, 2022, the team used a combination of molecular techniques to conduct experiments on lung epithelial cells of patients with cystic fibrosis and non-cystic fibrosis cells.
Their findings indicated that the cell surface expression of SIGIRR was significantly lower in CF epithelial cells than in non-CF epithelial cells. To their surprise, they also observed high expression of an alternative spliced SIGIRR isoform called ∆8-SIGIRR, in cystic fibrosis lung epithelial cells.
“We discovered that ∆8-SIGIRR is formed as a result of a dysfunction in mRNA splicing, which results in the loss of a segment of DNA known as exon-8 from the full-length SIGIRR, known as WT-SIGIRR,” notes Professor Shoto while discussing this unique discovery.
Upon further analysis, the team found that increased expression of ∆8-SIGIRR on the cell membrane of CF lung epithelial cells reduced WT-SIGIRR expression and function, demonstrating its dominant negative effect. Because of this decreased expression, WT-SIGIRR is unable to activate IL-37b – an anti-inflammatory molecule that inhibits TLRs, resulting in severe inflammation associated with cystic fibrosis.
This defect in IL37-SIGIRR signaling leading to persistent activation of inflammatory receptors is an exciting new discovery of the mechanisms underlying cystic fibrosis-related inflammation.
So, what are the long-term implications of these findings? “Our findings will lead to a deeper understanding of the pathological function of ∆8-SIGIRR in cystic fibrosis. Naturally, this will pave the way for the development of new drugs targeting SIGIRR for previously unknown targets of cystic fibrosis-related inflammation,” says Professor Shuto.
We hope this discovery will lead to the development of new and effective drugs and provide much-needed relief to cystic fibrosis patients!
About Associate Professor Tsuyoshi Shoto
Dr. Tsuyoshi Shoto received his Ph.D. in 2006 from Kumamoto University, Japan, where he is currently an associate professor at the Graduate School of Pharmaceutical Sciences. His research interests lie broadly in the areas of cell biology, genetics, immunology, histology, molecular biology, and neuroscience. Recently, his research has focused on lung diseases such as COPD, cystic fibrosis, and more. He has published more than 75 papers in prestigious international journals, which have been cited by researchers from all over the world.
International Journal of Molecular Sciences
A splice switch in SIGIRR causes a defect in IL-37-dependent anti-inflammatory activity in cystic fibrosis epithelial cells.
The date the article was published
July 13, 2022
The authors declare no conflict of interest
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