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 digests 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 programs are increased in IPF compared to non-diseased controls—type I interferon-activated and fibrotic remodeling programs. At cell, organ, and patient levels, cell types with increased type I interferon-activated program ( FABP4 hi alveolar macrophages, classical monocytes, interstitial macrophages, and/or non-classical monocytes) are associated with architecturally better-preserved lung tissue, the alveolar barrier, and less fibrotic lung, or less severe disease. Circulating monocytes exhibit heightened type I interferon response that inversely correlate with severity of clinical disease. Our findings show that myeloid cells with increased type I interferon-activated gene programs are associated with less fibrotic stages of IPF.