Delicate regulation of IL-1β-mediated inflammation by cyclophilin A
Wenxian Yang, Xiaoyuan Bai, Xiaohan Luan, Jie Min, Xiaodong Tian, Heqiao Li, Huizi Li, Wenqiang Sun, Wei Liu, Wenhui Fan, Wenjun Liu, Lei Sun
Abstract
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.