Role of type I interferon in pulmonary inflammation and fibrosis

Pulmonary fibrosis is a severe and potentially fatal lung disorder characterized by progressive respiratory dysfunction, imposing significant burdens on both society and affected families. This condition frequently occurs secondary to other diseases, particularly autoimmune disorders, where the development of interstitial lung disease (ILD) and subsequent fibrosis often leads to rapid clinical deterioration and poor prognosis. The irreversible nature of pulmonary fibrosis and the rapid progression of interstitial pneumonia underscore the need to investigate key molecular pathways involved in pathogenesis. Clinical studies have revealed elevated type I interferon (IFN-I) pathway activity in autoimmune patients with ILD compared to those without pulmonary involvement, with IFN-I levels positively correlating with disease severity, suggesting a potential pathogenic role in lung disease progression. However, current research on IFN-I in pulmonary diseases remain largely limited to its clinical association with ILD or its role in infectious pulmonary conditions. To define the function of IFN-I in non-infectious pulmonary inflammation and fibrosis, a bleomycin (BLM)-induced pulmonary fibrosis mouse model was employed. Our results demonstrated that Ifnar1-/- mice exhibited significantly improved survival and attenuated pulmonary inflammation and fibrosis compared to wild-type controls following high-dose BLM challenge. Subsequent cell-type-specific analysis revealed that hematopoietic-derived IFN-I signaling plays a central role in driving fibrosis, whereas IFN-I signalling in individual immune cell populations, such as macrophages or T cells, contributed modestly to disease progression. These findings provide direct experimental evidence that IFN-I promotes pulmonary inflammation and fibrosis, with hematopoietic cells serving as the principal mediators, through coordinated actions of multiple immune cell types rather than any single cellular subset. Furthermore, by analyzing the transcriptomic profile, IFN-I pathways were upregulated in peripheral blood of MDA5+ DM-ILD patients. To mimic the activated IFN-I signaling in autoimmune disease-related ILD, a poly (I: C)-BLM dual-hit model was applied, showing that robust IFN-I activation exacerbated pulmonary fibrotic progression, confirming IFN-I’s pro-fibrotic role. This study identifies IFN-I as an important modifier of pulmonary fibrogenesis and provides mechanistic insights into its role in the pathogenesis of rapidly progressive ILD and pulmonary fibrosis.

Author dc:creator

• Zhang, Yichi

Advisors dc:contributor.advisor

• Lu, Linrong
• Sloan, Richard
• Brook, Matthew

• IFN-I
• pulmonary fibrosis
• autoimmune diseases
• Macrophage
• T cell

Licence dc:rights.uri

• https://creativecommons.org/licenses/by/4.0/

Language dc:language.iso

en

Identifier URI

https://doi.org/10.7488/era/7422

OAI identifier oai:identifier

oai:era.ed.ac.uk:1842/44907