Cyclophilin A synergizes with MIP-2 to augment pro-inflammatory leukocyte recruitment (140.5)

Abstract

Chemokines contribute to inflammatory responses by inducing leukocyte migration and extravasation. Extracellular cyclophilins are a group of alternative chemokines that can be elevated during inflammation, and we have previously shown that their inhibition 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 work with other chemokines in vivo, recombinant extracellular CypA was co-delivered with intranasal LPS and lung neutrophil numbers were examined at a time point when two classical chemokines, MIP-2 and KC, but not CypA, are present. The addition of CypA induced a significant increase in early neutrophil recruitment that was greater than the additive recruitment induced by LPS and CypA alone. Boyden chamber chemotaxis assays in which purified mouse neutrophils were incubated with various combinations of CypA plus MIP-2 or KC were used to show that CypA had the capacity to synergize with MIP-2, but not KC, to induce augmented neutrophil migration. These findings provide a potential explanation for why the inhibition of cyclophilin activity in vivo has such a great impact on cell recruitment.