The deubiquitinase UCHL3 mediates p300-dependent chemokine signaling in alveolar type II cells to promote pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal, fibrotic, interstitial lung disease of unknown cause. Despite extensive studies, the underlying mechanisms of IPF development remain unknown. Here, we found that p300 was upregulated in multiple epithelial cells in lung samples from patients with IPF and mouse models of lung fibrosis. Lung fibrosis was significantly diminished by the alveolar type II (ATII) cell-specific deletion of the p300 gene. Moreover, we found that ubiquitin C-terminal hydrolase L3 (UCHL3)-mediated deubiquitination of p300 led to the transcriptional activation of the chemokines Ccl2, Ccl7, and Ccl12 through the cooperative action of p300 and C/EBP & beta;, which consequently promoted M2 macrophage polarization. Selective blockade of p300 activity in ATII cells resulted in the reprogramming of M2 macrophages into antifibrotic macrophages. These findings demonstrate a pivotal role for p300 in the development of lung fibrosis and suggest that p300 could serve as a promising target for IPF treatment. Lung disease: role of a control protein in pulmonary fibrosisResearchers investigating idiopathic pulmonary fibrosis (IPF), a chronic and potentially fatal lung disease of unknown cause, have identified increased levels of the epigenetic regulator protein p300 in lung cells from IPF patients and in a mouse model of the disease. The team led by Hyo Sup Shim and Ho-Geun Yoon at Yonsei University, Seoul, South Korea, also found that lung fibrosis (scar tissue formation) was significantly reduced in mice lacking the gene for p300. Chemically inhibiting p300 activity promoted the reprogramming of cells called macrophages into types able to reduce the formation of fibrosis. The research also uncovered a variety of molecular interactions involved in the initiation of fibrosis by p300, suggesting a pivotal role for the protein. Drugs targeting the production or activity of p300 might offer new approaches to treatment.