Newly Identified Defect Adds to Hyperinflammation in CF Lung Cells

A defect in an anti-inflammatory pathway called IL-37-SIGIRR contributes to the hyperinflammation seen in lung epithelial cells in patients with cystic fibrosis (CF), a new study suggests.

The study shows, for the first time, that a mutated form of the single immunoglobulin interleukin-1 receptor (IL-1R)-related molecule (SIGIRR), named delta 8-SIGIRR, is implicated in the inflammatory process in CF.

“Our findings will lead to a deeper understanding of the pathological [disease-causing] function of [delta 8]-SIGIRR in CF,” Tsuyoshi Shuto, PhD, an associate professor at the graduate school of pharmaceutical sciences at Kumamoto University, in Japan, and the senior author of the study, said in a press release.

“This will pave the way for the development of novel SIGIRR-targeting drugs for previously unknown targets of CF-associated inflammation,” Shuto said.

The research, “A Splice Switch in SIGIRR Causes a Defect of IL-37-Dependent Anti-Inflammatory Activity in Cystic Fibrosis Airway Epithelial Cells,” was published in the International Journal of Molecular Sciences.

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Defects in the interleukin-8 (IL-8) gene and increased IL-8 protein production are known to underlie excessive inflammation in CF. IL-8 is a cytokine — i.e., a small secreted protein important for cellular communication and the activation of the immune system — and a mediator of the inflammatory response.

Another critical factor contributing to CF-associated inflammation is the persistent activation of toll-like receptors (TLRs), proteins that play a key role in the body’s innate immune response. However, how TLR pathways contribute to CF inflammation is not completely understood.

Now, a research team in Japan demonstrated that the cell surface expression, or activity, of SIGIRR is much lower in CF lung epithelial cells than in non-CF epithelial cells. Epithelial cells are found on the surfaces of the body and act as a protective barrier. SIGIRR is a protein that suppresses TLRs and IL-1 signaling — IL-1 is a pro-inflammatory cytokine.

In turn, the researchers found, CF epithelial cells have higher levels of a mutated-SIGIRR form, named delta 8-SIGIRR, which interferes with the cell surface expression of normal SIGIRR. Reduced SIGIRR levels at the cell surface impair the activation of IL-37, an anti-inflammatory molecule that inhibits TLRs, therefore contributing to the inflammatory scenario associated with CF.

In sum, “the identification of the anti-inflammatory IL-37b-SIGIRR axis as one of the defective signals in CF cells provides a novel insight into understanding CF inflammation,” the researchers wrote.

The mutated delta 8-SIGIRR also is implicated in the development of human colorectal cancer and can potentially serve as a prognosis marker in this disease.

According to the team, “understanding the pathological relevance of [delta 8]-SIGIRR in other diseases opens up a new paradigm in the development of novel SIGIRR-targeting drugs.”

Models for other inflammatory diseases, such as rheumatoid arthritis, and other airway-inflammatory disorders (e.g., asthma, allergic rhinitis), also show reduced IL-37 levels. Treatment with recombinant IL-37 has been shown to exert an anti-inflammatory action in a mouse model of arthritis.

“Overall, our study encourages IL-37 activation (modulation) as a potential novel therapeutic tool against CF,” the team concluded.