Type I interferon–activated myeloid states are associated with less fibrotic stages in idiopathic pulmonary fibrosis

Early immune processes in idiopathic pulmonary fibrosis (IPF) are poorly defined. Here, we integrate single cell transcriptomics of lung digest and bronchoalveolar-lavaged cells (n=108 patients), subcellular-resolution tissue spatial transcriptomics, and single-cell phospho-CyTOF of blood cells to define myeloid states associated with early stages of fibrosis. Two distinct myeloid gene transcriptional programmes are increased in IPF compared to non-diseased controls - type I interferon-activated and fibrotic remodelling programme. At cell, organ and patient levels, cell types with increased type I interferon-activated programme (FABP4hi alveolar macrophages, classical monocytes, interstitial macrophages and non-classical monocytes) are associated with architecturally better-preserved lung tissue, the alveolar barrier and less fibrotic lung, or less severe disease. Circulating monocytes exhibited heightened type I interferon responsiveness that inversely correlated with severity of clinical disease. Our findings show that myeloid cells with increased type I interferon-activated gene programmes are associated with less fibrotic stages of IPF.