Cyclophilin A secreted from fibroblast-like synoviocytes is involved in the induction of CD147 expression in macrophages of mice with collagen-induced arthritis

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Abstract

Background

Cyclophilin A (CypA), a member of the immunophilin family, is a ubiquitously distributed intracellular protein. Recent studies have shown that CypA is secreted by cells in response to inflammatory stimuli. Elevated levels of extracellular CypA and its receptor, CD147 have been detected in the synovium of patients with RA. However, the precise process of interaction between CypA and CD147 in the development of RA remains unclear. This study aimed to investigate CypA secretion from fibroblast-like synoviocytes (FLS) isolated from mice with collagen-induced arthritis (CIA) and CypA-induced CD147 expression in mouse macrophages.

Findings

CIA was induced by immunization with type II collagen in mice. The expression and localization of CypA and CD147 was investigated by immunoblotting and immunostaining. Both CypA and CD147 were highly expressed in the joints of CIA mice. CD147 was expressed in the infiltrated macrophages in the synovium of CIA mice. In vitro, spontaneous CypA secretion from FLS was detected and this secretion was increased by stimulation with lipopolysaccharide. CypA markedly increased CD147 levels in macrophages.

Conclusions

These findings suggest that an interaction in the synovial joints between extracellular CypA and CD147 expressed by macrophages may be involved in the mechanisms underlying the development of arthritis.

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Most cited references 20

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Cyclophilin A enhances vascular oxidative stress and development of angiotensin II-induced aortic aneurysms

Kimio Satoh, Patrizia Nigro, Tetsuya Matoba … (2009)

Inflammation and oxidative stress are pathogenic mediators of many diseases, but therapeutic targets remain elusive. In the vasculature, abdominal aortic aneurysm (AAA) formation critically involves inflammaton and matrix degradation. Cyclophilin A (CyPA, encoded by Ppia) is highly expressed in vascular smooth muscle cells (VSMC), is secreted in response to reactive oxygen species (ROS), and promotes inflammation. Using the angiotensin II (AngII)-induced AAA model in Apoe −/− mice, we show that Apoe −/− Ppia −/− mice were completely protected from AngII–induced AAA formation, in contrast to Apoe −/− Ppia +/+ mice. Apoe −/− Ppia −/− mice showed decreased inflammatory cytokine expression, elastic lamina degradation, and aortic expansion. These features were not altered by reconstitution of bone marrow cells from Ppia +/+ mice. Mechanistic studies demonstrated that VSMC-derived intracellular and extracellular CyPA were required for ROS generation and matrix metalloproteinase-2 activation. These data define a novel role for CyPA in AAA formation and suggest CyPA is a new target for cardiovascular therapies.

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Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis.

Shahla Abdollahi-Roodsaz, Leo Joosten, Mieke F Roelofs … (2007)

Degeneration of extracellular matrix of cartilage leads to the production of molecules capable of activating the immune system via Toll-like receptor 4 (TLR-4). The objective of this study was to investigate the involvement of TLR-4 activation in the development and progression of autoimmune destructive arthritis. A naturally occurring TLR-4 antagonist, highly purified lipopolysaccharide (LPS) from Bartonella quintana, was first characterized using mouse macrophages and human dendritic cells (DCs). Mice with collagen-induced arthritis (CIA) and mice with spontaneous arthritis caused by interleukin-1 receptor antagonist (IL-1Ra) gene deficiency were treated with TLR-4 antagonist. The clinical score for joint inflammation, histologic characteristics of arthritis, and local expression of IL-1 in joints were evaluated after treatment. The TLR-4 antagonist inhibited DC maturation induced by Escherichia coli LPS and cytokine production induced by both exogenous and endogenous TLR-4 ligands, while having no effect on these parameters by itself. Treatment of CIA using TLR-4 antagonist substantially suppressed both clinical and histologic characteristics of arthritis without influencing the adaptive anti-type II collagen immunity crucial for this model. Treatment with TLR-4 antagonist strongly reduced IL-1beta expression in articular chondrocytes and synovial tissue. Furthermore, such treatment inhibited IL-1-mediated autoimmune arthritis in IL-1Ra(-/-) mice and protected the mice against cartilage and bone pathology. In the present study, we demonstrate for the first time that inhibition of TLR-4 suppresses the severity of experimental arthritis and results in lower IL-1 expression in arthritic joints. Our data suggest that TLR-4 might be a novel target in the treatment of rheumatoid arthritis.

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Cyclophilin A is a secreted growth factor induced by oxidative stress.

M Melaragno, J. Lambeth, Bradford C. Berk … (2000)

Reactive oxygen species have been implicated in the pathogenesis of atherosclerosis, hypertension, and restenosis, in part by promoting vascular smooth muscle cell (VSMC) growth. Many VSMC growth factors are secreted by VSMC and act in an autocrine manner. Here we demonstrate that cyclophilin A (CyPA), a member of the immunophilin family, is secreted by VSMCs in response to oxidative stress and mediates extracellular signal-regulated kinase (ERK1/2) activation and VSMC growth by reactive oxygen species. Human recombinant CyPA can mimic the effects of secreted CyPA to stimulate ERK1/2 and cell growth. The peptidyl-prolyl isomerase activity is required for ERK1/2 activation by CyPA. In vivo, CyPA expression and secretion are increased by oxidative stress and vascular injury. These findings are the first to identify CyPA as a secreted redox-sensitive mediator, establish CyPA as a VSMC growth factor, and suggest an important role for CyPA and enzymes with peptidyl-prolyl isomerase activity in the pathogenesis of vascular diseases.

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Author and article information

Journal

Journal ID (nlm-ta): J Inflamm (Lond)

Journal ID (iso-abbrev): J Inflamm (Lond)

Title: Journal of Inflammation (London, England)

Publisher: BioMed Central

ISSN (Electronic): 1476-9255

Publication date Collection: 2012

Publication date (Electronic): 20 November 2012

Volume: 9

Page: 44

Affiliations

[1 ]Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan

Article

Publisher ID: 1476-9255-9-44

DOI: 10.1186/1476-9255-9-44

PMC ID: 3542031

PubMed ID: 23167819

SO-VID: 9be085ee-ddbc-495b-abdd-69722504e7fd

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Cyclophilin A secreted from fibroblast-like synoviocytes is involved in the induction of CD147 expression in macrophages of mice with collagen-induced arthritis

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Abstract

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Most cited references 20

Cyclophilin A enhances vascular oxidative stress and development of angiotensin II-induced aortic aneurysms

Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis.

Cyclophilin A is a secreted growth factor induced by oxidative stress.

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