http://stroke.ahajournals.org/content/44/12/3498.abstract?etoc
Modulation by the PPARγ Agonist Rosiglitazone
- María Isabel Cuartero, PhD*;
- Iván Ballesteros, PhD*;
- Ana Moraga, BSc;
- Florentino Nombela, MD, PhD;
- José Vivancos, MD, PhD;
- John A. Hamilton, PhD;
- Ángel L. Corbí, PhD;
- Ignacio Lizasoain, MD, PhD;
- María A. Moro, PhD
+ Author Affiliations
- Correspondence to María A. Moro, PhD, Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Avenida Complutense s/n, 28040, Madrid, Spain. E-mail neurona@med.ucm.es
-
↵* Drs Cuartero and Ballesteros contributed equally.
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.
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