Mechanisms by which Cyclophilin-CD147 Interactions Contribute to Leukocyte Chemotaxis
Open AccessChemokines contribute to inflammatory responses by inducing leukocyte migration and extravasation. Extracellular cyclophilins are a group of alternative chemotactic factors that can be highly elevated during various inflammatory responses. We have previously shown that inhibition of cyclophilin activity reduces neutrophil infiltration by >40% in a mouse model of LPS-induced acute lung inflammation. Given the presence of many other chemokines during this inflammatory response, the observed potent contribution of cyclophilins led us to investigate whether they might function in a synergistic partnership with concurrent chemokines. To test whether cyclophilin A (CypA) can cooperate with other chemokines to promote leukocyte recruitment in vivo, recombinant extracellular CypA was co-delivered with intranasal LPS and changes in lung neutrophil numbers were then examined at a time point when two classical chemokines, MIP-2/CXCL2 and KC/CXCL1, but not endogenous CypA, are present in alveolar fluid. The addition of CypA induced a significant increase in early neutrophil recruitment that was greater than additive, suggesting that exogenous CypA might be mediating its augmenting effect by synergizing with endogenous chemokines. This possibility was confirmed using Boyden chamber chemotaxis assays in which purified mouse neutrophils were incubated with various combinations of CypA plus MIP-2 or KC. CypA had the capacity to synergize with MIP-2, but not KC, to induce augmented neutrophil migration. This increase in chemotaxis occurred only when CypA and MIP-2 were present concurrently in the chamber, not when neutrophils were pre-incubated with one before exposure to the other, supporting a synergistic, rather than a sequential, mechanism. CXCR2 receptor internalization and subsequent calcium flux and actin polymerization increased when neutrophils were stimulated with the combination of CypA and MIP-2, suggesting that the combination induces altered signaling. CD147 is the principal signaling receptor on human and mouse leukocytes for extracellular cyclophilins A and B and has been shown to be required for cyclophilin-mediated chemotaxis. CypA-induced chemotactic responses of leukocytes also depended on levels of CD147 expression with greater migration occurring in cell lines expressing higher levels of CD147.
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