Endothelial Hippo pathway regulates the neutrophil niche and lung fibrosis

Lung fibrosis is a severe disease with limited therapeutic options. The vascular niche is critical for lung function and fibrotic diseases, but the mechanisms by which endothelial cells (ECs) are regulated during lung injury and fibrosis remain largely unknown. As a critical regulatory pathway in lung development, regeneration, and fibrosis, the role of Hippo/YAP1 in the endothelial niche remains elusive. Here, we provide evidence that endothelial Hippo facilitates lung fibrosis via regulating the neutrophil niche. The YAP1 is activated in ECs of fibrotic lungs in mice and humans. Activating YAP1 via depleting the upstream repressor SAV1 in ECs promotes bleomycin-induced lung fibrosis, while endothelial YAP1 deficiency reverses lung fibrosis. Mechanism study reveals that endothelial YAP1 regulates the expression of CXCL1, which recruits CXCR2⁺ neutrophil in injured lungs. Blocking neutrophil recruitment via CXCR2 antagonist reduces lung fibrosis and blocks the effects of endothelial YAP1 activation. Therapeutically, inhibition of YAP1 with verteporfin reduces endothelial CXCL1 expression, neutrophil recruitment and lung fibrosis. Collectively, these findings demonstrate the roles of Hippo/YAP1 in regulating endothelial-neutrophil niche to participate in lung fibrosis.