Type I interferon-activated myeloid states are associated with less fibrotic stages in idiopathic pulmonary fibrosis.
Nathwani V., Weeratunga P., Woo J., Denney L., Vuppusetty C., Hu T., Zulfikar S., Achaiah A., Baghaarabani L., Parker H., Chuang H-W., Mazurczyk M., Fedorov A., Simmons A., Clelland C., Rehwinkel J., Antanaviciute A., Ho L-P.
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 (FABP4hi 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.