Type I IFN-activated lung monocytes and macrophages as initiators and drivers of fibrosis at the alveolar barrier in IPF
Nathwani, V.; Weeratunga, P.; Woo, J.; Denney, L.; Vuppusetty, C.; Hu, T.; Zulfikar, S.; Achaiah, A.; Parker, H.; Chuang, H.-w.; Mazurczyk, M.; Fedorov, A.; Simmons, A.; Clelland, C.; Rehwinkel, J.; Antanaviciute, A.; Ho, L.-p.
Show abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited therapeutic options. Although macrophages have been implicated in pathogenesis in murine models, their role in human disease remains unclear. Here, we present a comprehensive, unbiased single-cell transcriptomic and regulon atlas of myeloid cells from the alveolar barrier and lung tissue. We demonstrate that alveolar barrier macrophages are transcriptionally distinct from their lung tissue counterparts, exhibiting a striking upregulation of type I interferon (IFN) signalling in IPF. Circulating monocytes from IPF patients are primed for type I IFN responses, particularly in early disease, and monocytes are enriched with type I IFN-associated genes at lung sites of early fibrosis. These findings suggest a central role for type I IFN-activated monocytes in the initiation of fibrosis, and for alveolar barrier-related, type I IFN-activated macrophages in perpetuating fibrosis. These insights provide a rationale for therapeutically targeting monocytes in early stages of IPF.
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