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

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.

• Authors: Wenxian Yang, Xiaoyuan Bai, Xiaohan Luan, Jie Min, Xiaodong Tian, Heqiao Li, Huizi Li, Wenqiang Sun, Wei Liu, Wenhui Fan, Wenjun Liu, Lei Sun
• Journal: Cell reports (Cell Rep) Vol. 38 Issue 11 Pg. 110513 (03 15 2022) ISSN: 2211-1247 [Electronic] United States
• PMID: 35294882 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Interleukin-1beta
• Lipopolysaccharides
• Cyclophilin A

Topics

• Animals
• Cyclophilin A (metabolism)
• Inflammation (metabolism)
• Interleukin-1beta (metabolism)
• Lipopolysaccharides (metabolism, pharmacology)
• Mice
• Ubiquitination