Cyclophilins and CD147 in autoimmune arthritis Inflammatory destruction of target organs in autoimmune diseases, including rheumatoid arthritis (RA), begins with the emigration of effector cells from the microcirculation. Suppression of inflammatory leukocyte extravasation could provide protection against joint damage in RA. However, it is not well understood how immune cells gain access to the joints, and how the process of leukocyte recruitment to the synovium is regulated. The main regulators of leukocyte trafficking are chemokines, a family of chemoattracting cytokines that control cell migration and adhesion. Another, less appreciated, class of chemotactic agents are cyclophilins, a group of highly abundant cellular proteins mostly known as intracellular receptors for immunosuppressive drug, cyclosporine A, but also exerting extracellular activities. For example, cyclophilin A is a potent chemotactic agent for human T lymphocytes, eosinophils, monocytes, and neutrophils. Our studies identified CD147, previously characterized as an inducer of extracellular matrix metalloproteinases (MMPs), as a cell surface receptor for extracellular cyclophilins. However, the role of cyclophilins and CD147 in leukocyte trafficking and recruitment under physiological or pathological conditions is not known. We now propose to investigate the contribution of these proteins to autoimmune arthritis using collagen-induced arthritis (CIA) mouse model of rheumatoid arthritis. The following Specific Aims will be pursued:
Aim 1 : To reduce inflammation in CIA using modified cyclosporine A intervention;
Aim 2 : To characterize the chemotactic contribution of extracellular cyclophilins to CIA pathogenesis;
Aim 3 : To evaluate the contribution of the chemotactic versus the MMP-inducing activity of CD147 to CIA pathogenesis. Results of these studies will provide information on the mechanisms that regulate leukocyte trafficking in rheumatoid arthritis and will help identify and test therapeutic reagents that, by antagonizing leukocyte extravasation and reducing MMP production, could prevent inflammatory response and may also protect joint tissues from autoimmune inflammatory attacks even when the immune response has already been generated.
Cyclophilin and CD147 in autoimmune arthritis The proposed research is highly relevant to public health, as it addresses questions that are critical for understanding and treating rheumatoid arthritis, a dibilitating disease affecting more than 2 million people in US alone. These studies may suggest new approaches to treat rheumatoid arthritis by targeting extracellular cyclophilins and their receptor, CD147.
| Yurchenko, V; Constant, S; Eisenmesser, E et al. (2010) Cyclophilin-CD147 interactions: a new target for anti-inflammatory therapeutics. Clin Exp Immunol 160:305-17 |
| Malesevi?, Miroslav; Kühling, Jan; Erdmann, Frank et al. (2010) A cyclosporin derivative discriminates between extracellular and intracellular cyclophilins. Angew Chem Int Ed Engl 49:213-5 |
| Schlegel, Jennifer; Redzic, Jasmina S; Porter, Christopher C et al. (2009) Solution characterization of the extracellular region of CD147 and its interaction with its enzyme ligand cyclophilin A. J Mol Biol 391:518-35 |
