A20在巨噬细胞调节肺纤维化发病中的作用和机制

Pulmonary fibrosis is considered as not only an independent disorder but also the crucial pathological change in a diversity of chronic fibroproliferative lung diseases. Unfortunately, none medication was accepted to reverse fibrosis. As an important type of innate immune cell, macrophages can release kinds of inflammatory mediators which participate in the pathogenesis of PF. The ubiquitin-modifying enzyme A20 involves in many chronic inflammatory diseases through its regulating effect on immune cells. However, it is not clear how A20 influences the pathogenesis of PF through regulating macrophages activity. In early work, we found that repeated injury to the lung increased the expression of GSK-3β in macrophages. The enhanced GSK-3β interacted with and phosphorylated A20 to suppress its activity, which further induced macrophages activation to promote PF development. Restoring the A20 activity inhibited macrophages activation. Our project is trying to find the relationship of A20, macrophages and PF based on preliminary work. More importantly, screening the molecular probes that blocking GSK-3β/A20 interaction, and verifying the inhibitory effects of these probes on macrophages activation and PF development. Our work not only helps to understand the pathogenesis mechanism of PF but also provides a possibility for PF treatment by discovering new therapy target.

肺纤维化既是独立疾病，也是慢性纤维增生性肺病的基本病理改变。目前没有真正能够逆转肺纤维化的药物。巨噬细胞作为先天免疫细胞，可分泌多种炎性介质参与肺纤维化的发病。泛素化编辑酶A20调节细胞生物学功能参与许多炎性疾病过程。但A20是否调节巨噬细胞功能参与肺纤维化发病仍不清楚。我们发现，持续反复的肺损伤导致巨噬细胞中GSK-3β表达增加，过表达的GSK-3β诱导A20磷酸化并抑制其酶活性。受抑制的A20促进肺泡巨噬细胞的过度活化。恢复A20酶活性显著抑制巨噬细胞的活化。本项目拟在已有工作基础上深入探讨A20、巨噬细胞与纤维化发病之间的联系，特别是A20调节巨噬细胞活化的分子细胞生物学机制。我们希望发现能阻断GSK-3β/A20相互作用的分子探针，并验证其能否抑制巨噬细胞活化及肺纤维化发病。本项目不仅有助深入了解肺纤维化的发病机制，也将为发现新的抗肺纤维化药靶和先导化合物奠定理论基础。

尽管最近的研究对肺纤维化的发病机制提供了新见解，但目前肺纤维化疾病仍然缺乏有效治疗药物。肺泡巨噬细胞作为肺泡微环境中含量最多的免疫细胞，在纤维化的发生发展中发挥了重要的作用。本项目研究泛素修饰酶A20通过调节巨噬细胞促纤维化表型参与肺纤维化发病的作用和机制。本项目研究发现，慢性肺损伤诱导A20活性的抑制，导致肺泡巨噬细胞中C/EBPβ大量堆积，促进肺泡巨噬细胞向促纤维化表型的转化。通过深入研究，我们发现在肺纤维化组织中高表达的GSK-3β导致A20的磷酸化，抑制A20的酶活性，促进巨噬细胞的活化。在此基础上，我们筛选到抑制GSK-3β和A20结合的小分子多肽并证明该干扰肽对不同肺纤维化模型均产生很好的治疗效果。这项研究从全新角度阐释了肺纤维化发病的分子机制，不但鉴定和发现了GSK-3β/A20相互作用这一肺纤维化治疗的潜在新靶点，更发现了靶向该相互作用的治疗性化合物。相关工作已经完成并发表在免疫权威期刊Immunity（2019，IF = 31.745，第一作者）杂志。此外，作为上述工作的延伸和深化，我们揭示了巨噬细胞中TRIB3-GSK-3β-A20-C/EBPβ这一促纤维化信号环路在纤维化发病中的作用，特别是TRIB3调节GSK-3β表达的分子细胞生物学机制，相关工作发表在国际著名期刊Acta Pharmaceutica Sinica B（2021，IF = 11.614，第一兼共同通讯作者），并申请国内专利一项。