IL-25 Signaling Molecule Found to Contribute to Lung Inflammation, Fibrosis

A signaling molecule called interleukin-25 (IL-25) was found to support lung fibroblast proliferation and promote lung inflammation and fibrosis in mice, a study shows.

The findings suggest that blocking IL-25 may prevent many of the hallmark features of idiopathic pulmonary fibrosis (IPF), representing a new therapeutic target for this serious respiratory illness.

The study, “IL-25 contributes to lung fibrosis by directly acting on alveolar epithelial cells and fibroblasts,” was published in the journal Experimental Biology and Medicine.

IL-25 is a signaling protein produced by injured epithelial cells and innate immune cells. Studies have shown that this molecule can trigger immune responses that contribute to allergen-induced airway disease worsening, by promoting airway inflammation and tissue remodeling.

Also, IL-25 was found to be linked to lung fibrosis progression by supporting the recruitment of immune cells to the lungs. However, it is still unclear whether this signaling molecule itself can have pro-fibrotic activity.

Analysis of lung tissue samples collected from healthy people showed that IL-25 and its receptor (IL-25R) are occasionally detected in healthy tissues. In IPF patients, IL-25 and IL-25R are present at higher levels in lung tissues, mostly in infiltrated inflammatory cells and fibroblasts (cells of the connective tissue that are involved in the production of extracellular matrix and collagen).

To further explore IL-25’s contribution to lung fibrosis, Chinese researchers conducted a study in mice.

The team found that the signaling molecule could promote significant changes in the amount of some proteins known to be involved in the recruitment of immune cells.

In addition, when mice were exposed to high levels of IL-25, a pro-fibrotic and pro-inflammatory reaction was noted in their lungs, with increased deposition of collagen and progressive infiltration of immune cells — two hallmark features of IPF development.

After a series of experiments with cells in the lab, the team confirmed that IL-25 could effectively promote the proliferation of fibroblasts, as well as activate them to produce increased amounts of collagen — a key step in fibrosis development.

“We reported for the first time that IL-25/IL-25R axis is upregulated in injured alveolar epithelial cells and lung fibroblasts,” the researchers said.

Collectively, the results demonstrate that IL-25 “contributes to lung fibrosis by directly mediating alveolar epithelial cells/fibroblast activation,” they said.

The team was unable to correlate IL-25 effects with IPF clinical manifestations. Still, “treatment targeting IL-25 may be a novel method for treating IPF patients,” Huaping Dai, MD, from the China-Japan Friendship Hospital and the National Clinical Research Center for Respiratory Disease in Beijing, China, and the study’s co-author, said in a press release.

Additional studies are warranted to further understand the cellular processes triggered by IL-25 in the progression of lung fibrosis.