N2 Neutrophils, Novel Players in Brain Inflammation After Stroke Modulation by the PPARγ Agonist Rosiglitazone
N2 Neutrophils, Novel Players in Brain Inflammation After Stroke Modulation by the PPARγ Agonist Rosiglitazone
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DOI：
10.1161/strokeaha.113.002470
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发表时间：
2013-12-01
期刊：
影响因子：
8.3
通讯作者：
Moro, Maria A.
中科院分区：
文献类型：
--
作者：
Isabel Cuartero, Maria;Ballesteros, Ivan;Moro, Maria A.
背景和目的中性粒细胞传统上被认为是急性缺血性中风有害炎症反应的主要介质，但它们作为治疗靶点的潜力尚未得到探索。最近的证据表明，中性粒细胞可能获得不同的表型，并有助于通过释放抗炎介质来解决炎症。因此，类似于M2巨噬细胞，嗜中性粒细胞已被提出向N2表型转变，这是巨噬细胞中过氧化物酶体增殖物激活受体依赖性的极化。我们假设，过氧化物酶体增殖物激活受体激活与罗格列酮诱导的嗜酸性细胞动员和表型，可能会影响中风outcome.Methods脑切片和细胞悬液制备暴露于永久性远端大脑中动脉闭塞小鼠的变化。双重免疫染色与脑切片的体视学计数和脑细胞悬液的流式细胞仪分析performed.Results罗格列酮加速中性粒细胞浸润的缺血核心，伴随着神经保护。一些中性粒细胞（约31%）表达M2标志物，即Ym1和CD206（甘露糖受体）。用过氧化物酶体增殖物激活受体激动剂罗格列酮治疗后，大多数中性粒细胞（约77%）获得N2表型。有趣的是，罗格列酮增加中性粒细胞吞噬的小胶质细胞/巨噬细胞，清除，优先影响N2 subset.Conclusions我们提出的第一个证据，中性粒细胞重编程向N2表型在脑炎症，这可以通过激活过氧化物酶体增殖物激活受体-核受体。我们还表明，N2极化与增加中性粒细胞清除率，从而表明，这种开关是一个至关重要的事件，为解决炎症，可能参与神经保护。
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- dependent in macrophages. We hypothesize that peroxisome proliferator-activated receptor- 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 (approximate to 31%) expressed M2 markers, namely Ym1 and CD206 (mannose receptor). After treatment with the peroxisome proliferator-activated receptor- agonist rosiglitazone, most neutrophils (approximate to 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- 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.