
A recently created mouse model could unlock new biological understandings of interstitial pulmonary fibrosis (IPF). Kazuyo Moro, DDS, PhD, principal investigator at the RIKEN Center for Integrative Medical Sciences in Japan, led the team that developed the model and published a paper on its research findings in Nature Communications.
Dr. Moro began her research about 10 years ago when she began investigating the role that a special population of immune cells, known as group 2 innate lymphoid cells (ILC2s), play in the body’s response to lung infections. As part of that effort, she and her colleagues created mice lacking two key immune-related genes.
Without these genes, the mice exhibited defective signaling of a critical immune-modulating molecule called interferon-gamma, leading to enhanced activity of ILC2s and the associated inflammation that can spur allergic reactions. Intriguingly, these same mice also tended to develop fibrotic lesions in their lungs as they aged.
Now, Dr. Moro’s team has shown that the mouse model mimics the progression of IPF more closely than other mouse models of the lung disease. Unlike traditional models — where lung damage originates within the airways — these mice exhibit scarring on the lung’s lining (pleural side), mirroring the pathology observed in IPF patients. This unique aspect of the model offers unprecedented insights into IPF’s external triggers and progression.
“This is important for understanding why fibrosis begins in IPF patients,” said Dr. Moro. “Many basic researchers and pharma companies can now use this mouse model for drug development.”
The researchers showed that the lack of interferon-gamma signaling in these mice results in over-activation of ILC2s. These cells, in turn, express a receptor on their surface that promotes interactions with fibroblast cells on the outside of the lungs, leading to excess collagen production that can spur lung stiffness and tissue thickening.
Supporting evidence for the mouse data came from an interrogation of ILC2s isolated from the blood of IPF patients. As with mice, the patient-derived ILC2s exhibited elevated expression of the receptor needed to engage fibroblasts, along with decreased levels of a protein implicated in interferon-gamma signaling. The researchers also found that ILC2-activated fibroblasts initiate the production of IL-33, thereby reactivating ILC2s and setting up a positive feedback loop.
While these mice aren’t the perfect stand-in for IPF, they are more reflective of IPF than any commonly used model today, Dr. Moro said. She hopes that her team’s research can lead to the development of new treatments for the millions of patients who suffer from IPF worldwide.
Although the new mouse model can take about 15 weeks to develop signs of fibrosis (longer than other models), Dr. Moro said the benefits of biological accuracy far outweigh the convenience of speed.