Circulating human myeloid cells assume a profibrotic and tissue migratory-prone phenotype in Idiopathic pulmonary fibrosis

Despite increasing scientific and medical efforts, idiopathic pulmonary fibrosis (IPF) continues to be the most severe form of progressive pulmonary fibrosis that leads to death in 50% of patients 3-5 years after diagnosis. Increased circulating monocyte abundance is associated with IPF progression and mortality. The circulating phenotype and transcriptional profile of mononuclear myeloid cells, in IPF is unknown. To obtain a deeper resolution of myeloid cells, PBMC from IPF patients (n=9) and healthy controls (n=7) were split into two samples, complete PBMC and bead-enriched myeloid cells. Following single-cell RNA sequencing, unsupervised clustering identified an increased abundance of NK cells in PBMC of IPF vs controls. 7 clusters of circulating myeloid cells with unique transcriptomic profiles were identified. Cluster 0, 1, 2, 3, and 5 identified canonical classical and non-classical monocytes and circulating dendritic cells. RGCC, SLC11A1, and RPS26, genes associated with a pro-fibrotic macrophage phenotype in lung fibrosis, were significantly increased in IPF classical and non-classical monocytes. Cluster 4 defined interferon-regulated myeloid cells, previously associated with heart fibrosis. Cluster 6 identified platelet-affine myeloid cells, reported in kidney fibrosis models. Our study reports the first in-depth characterization of circulating myeloid subtypes in patients with IPF. Defining the transcriptomic profiles of myeloid subpopulations could potentially bring light to novel IPF driver mechanisms and personalized therapies.