Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Korea.
Department of Biomedical Laboratory Science, Yonsei University Mirae Campus, Wonju, South Korea.
Exp Mol Med. 2023 Aug;55(8):1795-1805. doi: 10.1038/s12276-023-01066-1. Epub 2023 Aug 1.
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/EBPβ, 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.
特发性肺纤维化（IPF）是一种病因不明的慢性、致命性、纤维性、间质性肺疾病。尽管进行了广泛的研究，但 IPF 发展的潜在机制仍不清楚。在这里，我们发现在 IPF 患者的肺样本和肺纤维化的小鼠模型中，多个上皮细胞中的 p300 被上调。通过肺泡 II 型（ATII）细胞特异性敲除 p300 基因，显著减轻了肺纤维化。此外，我们发现泛素 C 末端水解酶 L3（UCHL3）介导的 p300 去泛素化导致趋化因子 Ccl2、Ccl7 和 Ccl12 的转录激活，这是通过 p300 和 C/EBPβ 的协同作用实现的，进而促进 M2 巨噬细胞极化。选择性阻断 ATII 细胞中的 p300 活性导致 M2 巨噬细胞向抗纤维化巨噬细胞重编程。这些发现表明 p300 在肺纤维化的发展中起着关键作用，并表明 p300 可以作为治疗 IPF 的有前途的靶点。
