Cyclophilin A and MIP‐2 synergize to promote greater neutrophil migration

Abstract

Chemokines induced during inflammatory diseases contribute to the inflammatory response by inducing leukocyte migration and extravasation. Extracellular cyclophilins are an alternative group of proteins with chemokine activity. In previous studies, we have shown that extracellular cyclophilins are highly elevated during inflammatory responses and their inhibition reduces leukocyte infiltration by 40–50%. Such a major contribution by cyclophilins to leukocyte recruitment led us to investigate whether they might function synergistically with other chemokines. Using a mouse model of acute lung inflammation we first established the chemokines present concurrently with cyclophilin A (CypA) in inflamed lung airways and selected two (MIP‐2 and Gro1‐α) for further testing. Using in vitro Boyden chamber chemotaxis assays we determined that MIP‐2 synergizes with CypA to induce augmented neutrophil migration, but that Gro1‐α does not. The observed in vitro synergistic effects were confirmed in vivo by co‐injection of CypA and MIP‐2 into air pouches. These data provide evidence that CypA has the capacity to synergize with other chemokines present during inflammatory responses, potentially explaining the significant reduction in cell recruitment observed when cyclophilin activity is inhibited in vivo.This work was funded by NIH AI067254.