A revolutionary mouse model developed by RIKEN has provided researchers with a deeper understanding of the enigmatic lung disease known as idiopathic pulmonary fibrosis (IPF). The findings, recently published in Nature Communications, hold promise in unraveling new biological insights and accelerating the development of treatments for the millions globally affected by this debilitating condition.

IPF is a progressive lung disease characterized by scarring of the lungs, leading to a gradual decline in lung function and ultimately, to death. Despite its significant impact, the exact cause of IPF remains unknown, and there is currently no cure available.

The research, led by Kazuyo Moro and her team at the RIKEN Center for Integrative Medical Sciences, delved into the role of a unique group of immune cells called group 2 innate lymphoid cells (ILC2s) in response to lung infections. Through the development of mice lacking two crucial immune-related genes, the researchers uncovered that the absence of these genes resulted in impaired signaling of interferon-gamma, a vital immune-modulating molecule. This led to heightened activity of ILC2s and the subsequent inflammation associated with allergic reactions.

Interestingly, the mice with this genetic modification exhibited the formation of fibrotic lesions in their lungs as they aged, closely resembling the progression of IPF in humans. Unlike traditional mouse models where lung damage originates in the airways, these mice developed scarring on the pleural side of the lung lining, mirroring the pathology observed in IPF patients.

This distinctive characteristic of the mouse model offers a unique opportunity to gain insights into the external triggers and progression of IPF. Moro emphasized the significance of understanding the initiation of fibrosis in IPF patients, highlighting the potential for the mouse model to be utilized by both basic researchers and pharmaceutical companies in drug development efforts.

Further investigations by Moro’s team revealed that the absence of interferon-gamma signaling in these mice led to the hyperactivation of ILC2s. These cells expressed a receptor on their surface that facilitated interactions with fibroblast cells outside the lungs, resulting in excessive collagen production implicated in lung stiffness and tissue thickening.

Validation of the findings from the mouse model was obtained through an examination of ILC2s isolated from IPF patients’ blood. Similar to the mice, patient-derived ILC2s displayed elevated expression of the receptor necessary for engaging fibroblasts, along with reduced levels of a protein linked to interferon-gamma signaling.

Additionally, the researchers demonstrated that ILC2-activated fibroblasts initiated the production of IL-33, triggering a positive feedback loop by reactivating ILC2s.

Despite the drawback of a longer timeframe (around 15 weeks) for the mice to develop fibrosis compared to other models, Moro emphasized that the biological accuracy provided by this model outweighs the convenience of speed. The novel mouse model offers a more faithful representation of IPF, shedding light on the complex mechanisms underlying this devastating lung disease and paving the way for potential therapeutic advancements.

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1. Source: Coherent Market Insights, Public sources, Desk research.
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