CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China.
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; School of Life Sciences, University of Science and Technology of China, Hefei 230026, China.
Cell Rep. 2022 Mar 15;38(11):110513. doi: 10.1016/j.celrep.2022.110513.
The inflammatory response is tightly regulated, but its regulatory principles are still incompletely understood. Cyclophilin A (CypA) has long been considered as a pro-inflammatory factor. Here, we discover how CypA precisely regulates interleukin-1β (IL-1β)-mediated inflammatory responses. In lipopolysaccharide-treated mice, CypA deficiency initially inhibits and then promotes lung inflammation, which is closely related to IL-1β production. Mechanistically, CypA not only facilitates pro-IL-1β processing by increasing Smurf1-mediated K63-linked ubiquitination in an ATP-dependent manner but also accelerates pro-IL-1β degradation, depending on Smurf1-mediated K48-linked ubiquitination. Moreover, in IL-1β-treated mice, CypA exacerbates lung injury by enhancing cytokine production. It also upregulates the ILK/AKT pathway by inhibiting Cyld-mediated K63-linked ILK deubiquitination, which promotes the epithelial-mesenchymal transition (EMT) to facilitate lung repair. Collectively, CypA promotes inflammation activation by increasing IL-1β production and then promotes inflammation resolution by enhancing redundant pro-IL-1β degradation and IL-1β-induced EMT, indicating the complex and delicate regulation of inflammatory response.
炎症反应受到严格调控，但调控原理仍不完全清楚。亲环素 A（CypA）长期以来一直被认为是一种促炎因子。在这里，我们发现 CypA 如何精确调控白细胞介素 1β（IL-1β）介导的炎症反应。在脂多糖处理的小鼠中，CypA 缺乏最初抑制随后促进肺部炎症，这与 IL-1β的产生密切相关。在机制上，CypA 不仅通过增加 Smurf1 介导的 K63 连接泛素化以依赖 ATP 的方式促进 pro-IL-1β的加工，还通过 Smurf1 介导的 K48 连接泛素化加速 pro-IL-1β降解。此外，在 IL-1β处理的小鼠中，CypA 通过增强细胞因子的产生来加重肺损伤。它还通过抑制 Cyld 介导的 K63 连接的 ILK 去泛素化来上调 ILK/AKT 通路，促进上皮-间充质转化（EMT）以促进肺修复。总之，CypA 通过增加 IL-1β的产生来促进炎症激活，然后通过增强冗余的 pro-IL-1β降解和 IL-1β诱导的 EMT 来促进炎症消退，表明炎症反应受到复杂而精细的调控。
