title: Annexin A1 modulates natural and glucocorticoid-induced resolution of inflammation by enhancing neutrophil apoptosis.
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.
authors.affiliation: Programa de Pós-Graduação em Biologia Celular, Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Juliana P
authors.initials: JP
authors.lastname: Vago
authors.forename: Camila R C
authors.initials: CR
authors.lastname: Nogueira
authors.forename: Luciana P
authors.initials: LP
authors.lastname: Tavares
authors.forename: Frederico M
authors.initials: FM
authors.lastname: Soriani
authors.forename: Fernando
authors.initials: F
authors.lastname: Lopes
authors.forename: Remo C
authors.initials: RC
authors.lastname: Russo
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pinho
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
authors.forename: Lirlândia P
authors.initials: LP
authors.lastname: Sousa
mesh_terms: D000208:Acute Disease; D000818:Animals; D017305:Annexin A1 / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology*; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000494:pharmacology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D017305:Annexin A1; D005938:Glucocorticoids; D018836:Inflammation Mediators; C573274:annexin A1, mouse; D003907:Dexamethasone