The major theme of this research is to identify novel factors regulating leukocyte trafficking during inflammatory responses. Leukocyte trafficking and recruitment are critical components of inflammation-mediated pathology. The main regulators of leukocyte trafficking are chemokines, a family of chemoattracting cytokines. Another less appreciated class of chemotactic agents is cyclophilins, a group of highly abundant cellular proteins mostly known as receptors for the immunosuppressive drug, cyclosporin A. Both cyclophilins A (CypA) and B (CypB) have been found to induce signaling responses in target cells. Secreted CypA is a potent neutrophil and eosinophil chemoattractant in vitro and elicits a potent inflammatory response when injected in vivo, characterized by a rapid influx of neutrophils. Recent studies have demonstrated that CypB induces chemotaxis of memory CD4+ T cells. Such findings suggest a potential role for extracellular cyclophilins as chemotactic factors during inflammatory responses. Indirect evidence that cyclophilins contribute to inflammation-mediated pathology is provided by several disease models, including rheumatoid arthritis and vascular smooth muscle disease, in which elevated levels of cyclophilins are observed at the site of inflammation. Thus, extracellular cyclophilins provide a potentially novel target for therapeutic intervention during inflammatory responses. Our group has previously identified CD147 as the receptor for cyclophilins A and B. CD147 is present on most hematopoietic cells and is required for cyclophilin-induced signaling and chemotaxis. The objective of the proposed research is to determine the contribution of cyclophilin-CD 147 interactions in leukocyte recruitment during inflammatory responses. Specifically, we will establish how blocking cyclophilin-CD 147 interactions impacts on the chemotactic responses of neutrophils and memory CD4+ T cells to cyclophilins. This will be examined using both in vitro and in vivo approaches, the latter using a mouse model of lung inflammation. ? ?
| Yurchenko, Vyacheslav; Constant, Stephanie; Bukrinsky, Michael (2006) Dealing with the family: CD147 interactions with cyclophilins. Immunology 117:301-9 |
| Arora, Kamalpreet; Gwinn, William M; Bower, Molly A et al. (2005) Extracellular cyclophilins contribute to the regulation of inflammatory responses. J Immunol 175:517-22 |
