Extracellular cyclophilins in health and disease

Abstract

Background: Extracellular cyclophilins (eCyPs) are pro-inflammatory factors implicated in pathogenesis of a number of inflammatory diseases. Most pathogenic activities of eCyPs are related to their chemotactic action towards leukocytes, which is mediated by eCyP receptor on target cells, CD147, and involves peptidyl-prolyl cis-trans isomerase activity of cyclophilins. This activity is inhibited by cyclosporine A (CsA) and non-immunosuppressive derivatives of this drug. Accumulating evidence for the role of eCyPs in disease pathogenesis stimulated research on the mechanisms of eCyP-initiated events, resulting in identification of multiple signaling pathways, characterization of a variety of effector molecules released from eCyP-treated cells, and synthesis of CsA derivatives specifically blocking eCyPs. However, a number of important questions related to the mode of action of eCyPs remain unanswered.

Scope of review: In this article, we integrate available information on release and function of extracellular cyclophilins into a unified model, focusing on outstanding issues that need to be clarified.

Major conclusions: Extracellular cyclophilins are critical players in pathogenesis of a number of inflammatory diseases. Their mechanism of action involves interaction with the receptor, CD147, and initiation of a poorly characterized signal transduction process culminating in chemotaxis and production of pro-inflammatory factors.

General significance: Extracellular cyclophilins present an attractive target for therapeutic interventions that can be used to alleviate symptoms and consequences of acute and chronic inflammation. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets.

Keywords: CD147; Chemotaxis; Cyclosporine A; Disease model; Extracellular cyclophilin; Inflammation.

Fig. 1

Signaling interactions between extracellular cyclophilins and CD147. Interactions with CD147 are shown for eCyPA and eCyPB, and receptor for eCyPC remains unknown. Signaling is induced by isomerization of Pro²¹¹ bonds by eCyPA and Pro¹⁸⁰ bond by eCyPB, although it remains possible that eCyPB also targets Pro²¹¹. Isomerization alters the CD147 conformation inducing or changing its interaction with neighboring signal transducing molecules, such as CD98 and integrin β1 (the actual signaling molecule may be different in different cell types). Signals induced as a result of this process remain only partially characterized. Red question marks show the key gaps in our knowledge. More details are in the text.

Fig. 2

Extracellular cyclophilins in allergic lung inflammation. Mice were primed by intraperitoneal (i.p.) injection of ovalbumin (OVA) in alum, and challenged with OVA intranasally (i.n.). Groups of OVA-primed/challenged mice were sacrificed every other day starting at day 6 through day 16 of the inflammatory response. Numbers of effector/memory CD4⁺ T cells and eosinophils were determined in BAL fluid and lung tissue of individual mice by flow cytometric analysis, and are presented as mean ± SE, with n = 10 mice per time point. CyPA and CyPB analysis was performed by Western blot on cleared fluid from individual BAL samples, and results are presented as mean ± SE gel band density (GBD) for each time point as determined by densitometric analysis.