N2 neutrophils, novel players in brain inflammation after stroke: modulation by the PPARγ agonist rosiglitazone.
Stroke
; 44(12): 3498-508, 2013 Dec.
Article
em En
| MEDLINE
| ID: mdl-24135932
ABSTRACT
BACKGROUND AND PURPOSE:
Neutrophils have been traditionally recognized as major mediators of a deleterious inflammatory response in acute ischemic stroke, but their potential as a therapeutic target remains unexplored. Recent evidence indicates that neutrophils may acquire different phenotypes and contribute to resolution of inflammation through the release of anti-inflammatory mediators. Thus, similar to M2 macrophages, neutrophils have been proposed to shift toward an N2 phenotype, a polarization that is peroxisome proliferator-activated receptor-γ dependent in macrophages. We hypothesize that peroxisome proliferator-activated receptor-γ activation with rosiglitazone induces changes in neutrophilic mobilization and phenotype that might influence stroke outcome.METHODS:
Brain sections and cell suspensions were prepared from mice exposed to permanent distal middle cerebral artery occlusion. Double immunostaining with stereological counting of brain sections and flow-cytometry analysis of brain cell suspensions were performed.RESULTS:
Rosiglitazone accelerated neutrophil infiltration to the ischemic core, concomitantly to neuroprotection. Some neutrophils (≈31%) expressed M2 markers, namely Ym1 and CD206 (mannose receptor). After treatment with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone, most neutrophils (≈77%) acquired an N2 phenotype. Interestingly, rosiglitazone increased neutrophil engulfment by microglia/macrophages, a clearance that preferentially affected the N2 subset.CONCLUSIONS:
We present the first evidence of neutrophil reprogramming toward an N2 phenotype in brain inflammation, which can be modulated by activation of the peroxisome proliferator-activated receptor-γ nuclear receptor. We also show that N2 polarization is associated with an increased neutrophil clearance, thus suggesting that this switch is a crucial event for resolution of inflammation that may participate in neuroprotection.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Encéfalo
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Acidente Vascular Cerebral
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Infarto da Artéria Cerebral Média
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Tiazolidinedionas
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PPAR gama
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Encefalite
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Neutrófilos
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article