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J Leukoc Biol. 2012 Aug;92(2):249-58. doi: 10.1189/jlb.0112008. Epub 2012 Apr 9.

Annexin A1 modulates natural and glucocorticoid-induced resolution of inflammation by enhancing neutrophil apoptosis.

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1
Programa de Pós-Graduação em Biologia Celular, Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

Abstract

This study aimed at assessing whether AnxA1, a downstream mediator for the anti-inflammatory effects of GCs, could affect the fate of immune cells in tissue exudates, using LPS-induced pleurisy in BALB/c mice. AnxA1 protein expression in exudates was increased during natural resolution, as seen at 48-72 h post-LPS, an effect augmented by treatment with GC and associated with marked presence of apoptotic neutrophils in the pleural exudates. The functional relevance of AnxA1 was determined using a neutralizing antibody or a nonspecific antagonist at FPR/ALXRs: either treatment inhibited both spontaneous and GC-induced resolution of inflammation. Injection of Ac2-26 (100 μg, given 4 h into the LPS response), an AnxA1-active N-terminal peptide, promoted active resolution and augmented the extent of neutrophil apoptosis. Such an effect was prevented by the pan-caspase inhibitor zVAD-fmk. Mechanistically, resolution of neutrophilic inflammation was linked to cell apoptosis with activation of Bax and caspase-3 and inhibition of survival pathways Mcl-1, ERK1/2, and NF-κB. These novel in vivo data, using a dynamic model of acute inflammation, provide evidence that AnxA1 is a mediator of natural and GC-induced resolution of inflammation with profound effects on neutrophil apoptosis.

PMID:
22493082
DOI:
10.1189/jlb.0112008
[Indexed for MEDLINE]

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