Lead image: On the left, a CT scan image of IPF lungs with typical 'honeycomb scarring'. On the right, immunofluorescence analysis of representative microscopic lung tissue showing clumps of immune cells with increased type 1 interferon activity (orange-yellow colour) near the alveolar lining (white outline).

The study, published in Cell Reports, found an unexpected immune signal in the less fibrotic (scarred) regions of lungs affected by idiopathic pulmonary fibrosis (IPF) – a disease that is usually diagnosed after significant scarring has already occurred. These findings offer clues to how the disease develops before extensive lung scarring happens, and may help to identify new drugs to treat the condition sooner.

Researchers in the Ho Group used cutting-edge single-cell and spatial technologies to map a major group of immune cells (monocytes and macrophages) across the blood, alveolar surface and lung tissue of patients with IPF. These cells typically help the body respond to infection, but they can also influence inflammation and tissue repair.

The research team found that two distinct patterns of gene activity dominate these immune cells in the disease: one associated with fibrotic remodelling - the process by which lung tissue becomes scarred and its normal structure is disrupted - and the other driven by type I interferon activation, which was found in better-preserved and less fibrotic regions of the lung.

Type I interferons are best known for their role in antiviral immunity, making their prominence in IPF an unexpected finding.

Lead author Ling-Pei Ho, Professor of Respiratory Immunology in the MRC Translational Immune Discovery Unit, said:

What surprised us was how consistently this interferon signal appeared in the less fibrotic parts of the lung. It was present at the alveolar surface, in relatively preserved regions of lung tissue, and in circulating monocytes from patients with milder disease.

To complement their single-cell RNA sequencing analysis of 108 IPF and control lung samples, Professor Ho’s team used Xenium spatial transcriptomics to generate a high-resolution, unbiased single-cell map of IPF lung tissue.

This revealed reproducible cellular ‘neighbourhoods’ across different patients and showed that interferon-activated alveolar macrophages and monocytes were more plentiful in areas with less fibrotic remodelling.

The same pattern extended beyond the lung. Blood monocytes from people with IPF showed heightened responsiveness to interferon, while higher expression of interferon-related genes was associated with milder disease.

Professor Ho added:

Current treatments target fibrosis once scarring is already established. Our findings raise the possibility of therapeutically targeting immune pathways that are active at earlier stages of fibrosis and in patients with earlier disease before irreversible remodelling of the lungs.

 Read the full paper in Cell Reports: Type I interferon-activated myeloid states are associated with less fibrotic stages in idiopathic pulmonary fibrosis

The study was supported by the NIHR Oxford Biomedical Research Centre and the UKRI Medical Research Council.