Uncoupling Protein-2 Negatively Regulates Polymorphonuclear Leukocytes Chemotaxis via Modulating [Ca 2+ ] Influx

Abstract

Objective— Previous studies demonstrated that uncoupling protein 2 (UCP2) plays a negative role in modulating leukocyte inflammatory responses. The mechanism underneath the role of UCP2 in modulating leukocyte inflammatory responses, however, is incompletely understood. Here, we investigated the effect of UCP2 in polymorphonuclear leukocyte (PMN) chemotaxis. Methods and Results— First, we assessed PMN chemotaxis in zymosan-induced murine peritonitis and found that UCP2 −/− mice had significantly more migrated PMN in peritoneal lavage compared to their wild-type littermates. In vitro transmigration assays using isolated PMN also showed that PMN from UCP2 −/− mice migrated faster than those from wild-type mice in response to N-formyl-methionyl-leucyl-phenylalanine (fMLP). Second, in supporting an inhibitory role of UCP2 in PMN transmigration, migrated PMN had a decreased UCP2 expression compared to nonmigrated PMN. In contrast, in streptozotocin-induced diabetic mice in which UCP2 expression was enhanced, PMN chemotaxis was reduced. Third, comparing to UCP2 +/+ PMN, UCP2 −/− PMN had a stronger upregulation of fMLP-induced surface CD11b/CD18 and CD11a/CD18. Finally, UCP2 −/− PMN showed a quicker and larger fMLP-triggered intracellular calcium mobilization compared to UCP2 +/+ PMN. Conclusion— Our study demonstrates that UCP2 serves as a brake in controlling PMN chemotaxis and that the effect of UCP2 on PMN chemotaxis may be through modulating calcium influx.