Neutrophil extracellular traps sustain inflammation and myofibroblast activation to drive lung fibrosis – FibroNETs

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix (ECM) by myofibroblasts, leading to impaired gas exchange and ultimately death due to lack of effective treatments. Fibrosis is a feature of most chronic inflammatory diseases. We recently identified the presence Neutrophil Extracellular Traps (NETs) in humans with IPF and in the bleomycin-induced lung fibrosis mouse model. We identified a loop between NETs, macrophages and fibroblasts that drives and sustains lung inflammation and lung fibrosis. Specifically, macrophages-derived interleukin-1 beta induces NET formation, while NETs in turn induce macrophage activation, exacerbating lung inflammation. Additionally, NETs trigger myofibroblast activation, leading to ECM remodeling and fibrosis, while this fibrotic ECM in turn promotes further NET formation, exacerbating lung fibrosis. In aim 1, we will identify the cellular and molecular mechanisms driving and sustaining the loop between NETs and macrophages. In aim 2, we will determine the cellular and molecular mechanisms regulating the loop between NETs, fibroblasts and the ECM. Identifying these mechanisms will be the foundation for future development of new therapies for lung fibrosis.