GATA1-defective immune-megakaryocytes as possible drivers of idiopathic pulmonary fibrosis

Abstract

SummaryIdiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disorder with limited therapeutic options. Insufficient understanding of driver mutations and poor fidelity of currently available animal models has limited the development of effective therapies. Since GATA1 deficient megakaryocytes sustain myelofibrosis, we hypothesized that they may also induce fibrosis in lungs. We discovered that lungs from IPF patients andGata1lowmice contain numerous GATA1negative immune-poised megakaryocytes that, in mice, have defective RNA-seq profiling and increased TGF-β1, CXCL1 and P-selectin content. With age,Gata1lowmice develop fibrosis in lungs. Development of lung fibrosis in this model is prevented byP-selectindeletion and rescued by P-selectin, TGF-β1 or CXCL1 inhibition. Mechanistically, P-selectin inhibition decreases TGF-β1 and CXCL1 content and increases GATA1positive megakaryocytes while TGF-β1 or CXCL1 inhibition decreased CXCL1 only. In conclusion,Gata1lowmice are a novel genetic-driven model for IPF and provide a link between abnormal immune-megakaryocytes and lung fibrosis.