The major theme of our research is to identify novel factors regulating leukocyte trafficking during inflammatory responses. The main regulators of leukocyte migration 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. In recent studies, cyclophilin A (CypA) was shown to be a chemotactic factor in vitro for several different leukocytes, including neutrophils, eosinophils and monocytes. Furthermore, CypA elicits a potent inflammatory response when injected in vivo, characterized by a rapid influx of leukocytes into tissues. Other studies have demonstrated that another cyclophilin, CypB, induces chemotaxis and specific adhesion of memory CD4+ T cells to the extracellular matrix. Taken together, such findings suggest a role for extracellular cyclophilins as chemotactic factors for cells associated with inflammatory responses. Our group has recently identified CD147 as the receptor for cyclophilins A and B and we have shown that CD147 is required for cyclophilin-induced signaling and chemotaxis. Our working hypothesis is that CypA and CypB, via interaction with CD147, directly contribute to leukocyte attraction to sites of inflammation. The objective of the proposed research is to establish the role of extracellular cyclophilins in the recruitment of leukocytes in inflammation-mediated pathogenesis. Specifically, we will investigate the contribution of cyclophilin-CD147 interactions to eosinophil and memory T cell recruitment during the effector phase of allergic asthma and we will establish whether inhibiting these interactions can reduce leukocyte infiltration into inflammed pulmonary tissues. The findings from these studies are the first step in identifying a novel target for therapeutic intervention in diseases mediated by inflammation.
| Yurchenko, Vyacheslav; Constant, Stephanie; Bukrinsky, Michael (2006) Dealing with the family: CD147 interactions with cyclophilins. Immunology 117:301-9 |
| Gwinn, William M; Damsker, Jesse M; Falahati, Rustom et al. (2006) Novel approach to inhibit asthma-mediated lung inflammation using anti-CD147 intervention. J Immunol 177:4870-9 |
