Delicate regulation of IL-1β-mediated inflammation by cyclophilin A

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-1 beta (IL-1 beta)-mediated inflammatory responses. In lipopolysaccharide-treated mice, CypA deficiency initially inhibits and then promotes lung inflammation, which is closely related to IL-1 beta production. Mechanistically, CypA not only facilitates pro-IL-1 beta processing by increasing Smurf1-mediated K63-linked ubiquitination in an ATP-dependent manner but also accelerates pro-IL-18 degradation, depending on Smurf1-mediated K48-linked ubiquitination. Moreover, in IL-1 beta-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-1 beta production and then promotes inflammation resolution by enhancing redundant pro-IL-1 beta degradation and IL-1 beta-induced EMT, indicating the complex and delicate regulation of inflammatory response.

Automated summary

The inflammatory response is regulated by complex and delicate mechanisms, with Cyclophilin A (CypA) playing a role in promoting both inflammation activation and resolution by affecting IL-1 beta production and the epithelial-mesenchymal transition (EMT).