|ZFIN ID: ZDB-PUB-110523-25|
Activation of hypoxia-inducible factor-1α (Hif-1α) delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model
Elks, P.M., van Eeden, F.J., Dixon, G., Wang, X., Reyes-Aldasoro, C.C., Ingham, P.W., Whyte, M.K., Walmsley, S.R., and Renshaw, S.A.
|Source:||Blood 118(3): 712-22 (Journal)|
|Registered Authors:||Elks, Phil, Ingham, Philip, Renshaw, Steve A., van Eeden, Freek, Wang, Xingang|
|PubMed:||21555741 Full text @ Blood|
Elks, P.M., van Eeden, F.J., Dixon, G., Wang, X., Reyes-Aldasoro, C.C., Ingham, P.W., Whyte, M.K., Walmsley, S.R., and Renshaw, S.A. (2011) Activation of hypoxia-inducible factor-1α (Hif-1α) delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model. Blood. 118(3):712-22.
ABSTRACTThe oxygen sensing transcription factor HIF-1α plays a critical role in the regulation of myeloid cell function. The mechanisms of regulation are not well understood, nor the phenotypic consequences of HIF modulation in the context of neutrophilic inflammation. Species conservation across higher metazoans enables the use of the genetically tractable and transparent zebrafish embryo to study in vivo resolution of the inflammatory response. Using both a pharmacological approach known to lead to stabilization of HIF-1α, and selective genetic manipulation of zebrafish HIF-1α homologues we sought to determine the roles of HIF-1α in inflammation resolution. Both approaches reveal that activated Hif-1α delays resolution of inflammation following tail transection in zebrafish larvae. This delay can be replicated by neutrophil specific Hif activation, and is a consequence of both reduced neutrophil apoptosis, and increased retention of neutrophils at the site of tissue injury. Hif-activated neutrophils continue to patrol the injury site during the resolution phase, when neutrophils would normally migrate away. Site-directed mutagenesis of Hif in vivo reveals that hydroxylation of Hif-1α by Phd hydroxylases critically regulates the Hif pathway in zebrafish neutrophils. Our data demonstrate that Hif-1α regulates neutrophil function in complex ways during inflammation resolution in vivo.