Leukocyte trafficking and recruitment is a critical component of inflammation-mediated pathology. 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, cyclosporin A, but also exerting extracellular activities. For example, cyclophilin A (CypA) is a potent chemotactic agent for T lymphocytes, eosinophils, monocytes, and neutrophils. Our studies identified CD147 as a cell surface receptor for extracellular cyclophilins. However, the role of cyclophilin-CD147 interaction in leukocyte trafficking and recruitment under physiological or pathological conditions has not been investigated. We now propose to investigate CypA activity as a neutrophil chemoattractant in rheumatoid arthritis. CypA is released in the joints of rheumatoid arthritis patients, and neutrophil infiltration into synovial fluid is a recognized pathogenic factor in this disease. To test this hypothesis, we propose the following Specific Aims:
Specific Aim 1. To analyze CD147 expression on neutrophils and T lymphocytes from normal donors and rheumatoid arthritis patients and responses of these cells to cyclophilins.
Specific Aim 2. To determine the role of cyclophilin-CD147 interaction in neutrophil recruitment to the joints using an in vivo model of rheumatoid arthritis, collagen-induced arthritis (CIA) in mice. The studies proposed in this application represent a high degree of innovation because they explore a novel hypothesis, which proposes new regulating factors for leukocyte trafficking. If proven, this hypothesis might suggest novel approaches to treatment of rheumatoid arthritis and other inflammatory conditions. This exploratory proposal is fully consistent with the goals of this PA as it extends our previous discovery toward new directions related to regulation of inflammatory responses.
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