Extracellular cyclophilin A possesses chemotaxic activity in cattle.

Satoru Takanashi,Yoshio Kiku,Nanami Itaya,Tomohito Hayashi,Megumi Urakawa,Miku Abe,Katsuyoshi Sato,Hisashi Aso,Saori Umemura,Tao Zhuang,Michael T Rose,Tomonori Nochi,Kouichi Watanabe,Haruki Kitazawa

doi:10.1186/s13567-015-0212-1

Abstract

Cyclophilin A (CyPA) was originally discovered in bovine thymocytes as a cytosolic binding protein of the immunosuppressive drug cyclosporine A. Recent studies have revealed that in mice and humans, CyPA is secreted from cells in injured or infected tissues and plays a role in recruiting inflammatory cells in those tissues. Here we found that in cattle abundant level of extracellular CyPA was observed in tissues with inflammation. To aid in investigating the role of extracellular CyPA in cattle, we generated recombinant bovine CyPA (rbCyPA) and tested its biological activity as an inflammatory mediator. When bovine peripheral blood cells were treated with rbCyPA in vitro, we observed that rbCyPA reacts with the membranous surface of granulocytes, monocytes and lymphocytes. Chemotaxis analysis showed that the granulocytes migrate toward rbCyPA and the migration is inhibited by pre-treatment with an anti-bovine CyPA antibody. These results indicate that, as for mice and humans, extracellular CyPA possesses chemotactic activity to recruit inflammatory cells (e.g., granulocytes) in cattle, and could thus be a potential therapeutic target for the treatment of inflammation.

Highlights

Inflammation occurs when tissues are injured by exposure to pathogens or foreign substances [1]
Secretion of Cyclophilin A (CyPA) in mammary gland of cattle with mastitis As CyPA in mice and humans has been known to be secreted from cells during inflammation, such as abdominal aortic aneurysms (AAA), our initial study was designed to investigate whether extracellular CyPA was found in cattle during inflammation
When mammary gland tissues sampled from cattle with or without mastitis were analyzed by immunohistochemistry with the commercial anti-CyPA antibody, we found that, regardless of the presence of mastitis, CyPA was present in the cytoplasm of mammary epithelial cells (Figure 1)

Summary

Introduction

Inflammation occurs when tissues are injured by exposure to pathogens (e.g., bacteria, viruses) or foreign substances (e.g., toxins, chemicals) [1]. Chemokines, which are small cytokines sharing a basic structure composed of three antiparallel β-strands and an overlying α-helix, play a key role in regulating leucocyte trafficking into inflammatory tissues [2]. Recent studies have shown that, in addition to chemokines, other factors without the structural characteristics peculiar to the chemokines, are involved in leucocyte trafficking as they possess potent chemotactic activity [4]. Cyclophilin A (CyPA), which is the most abundant member of the family, has multiple biological roles in protein folding, trafficking, T cell activation and cell signaling [5]. CyPA had been believed to be present only in the intracellular space, but recent studies have shown that it is secreted from cells in response to hypoxia, infection and oxidative stress [8]. An example is that the reactive oxygen species induces CyPA secretion from vascular smooth muscle cells (VSMCs), resulting in the formation of abdominal aortic aneurysms (AAA), in which abnormal proliferation of VSMCs, unusual expression of endothelial cell adhesion molecule, and aberrant infiltration of inflammatory cells in the aortic wall are observed [9,10]

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Results

Conclusion