Conditional ablation of myeloid TNF increases lesion volume after experimental stroke in mice, possibly via altered ERK1/2 signaling.
Conditional ablation of myeloid TNF increases lesion volume after experimental stroke in mice, possibly via altered ERK1/2 signaling.
复制标题
DOI：
10.1038/srep29291
复制
发表时间：
2016-07-07
影响因子：
4.6
通讯作者：
Lambertsen KL
中科院分区：
文献类型：
--
作者：
Clausen BH;Degn M;Sivasaravanaparan M;Fogtmann T;Andersen MG;Trojanowsky MD;Gao H;Hvidsten S;Baun C;Deierborg T;Finsen B;Kristensen BW;Bak ST;Meyer M;Lee J;Nedospasov SA;Brambilla R;Lambertsen KL
小胶质细胞在脑缺血后被激活，并增加神经和免疫调节细胞因子肿瘤坏死因子（TNF）的产生。为了研究来自该细胞来源的 TNF 在局灶性脑缺血中的功能，我们使用了 TNF 条件敲除小鼠 (LysMcreTNFfl/fl)，其中髓系细胞（包括小胶质细胞）中的 TNF 基因被删除。该缺失使脂多糖刺激的培养原代小胶质细胞分泌的 TNF 水平降低了约 93%。此外，在首次处理的 LysMcreTNFfl/fl 小鼠中，磷酸化 ERK/ERK 比率显着降低，表明 ERK 信号转导发生了改变。局灶性脑缺血后立即使用 18[F]-氟脱氧葡萄糖进行的 Micro-PET 显示 LysMcreTNFfl/fl 小鼠的葡萄糖摄取增加，代表显着的代谢变化，与同窝小鼠 (TNFfl/fl) 相比，这转化为 24 小时和 5 天时梗塞体积的增加。在首次接触的 LysMcreTNFfl/fl 小鼠中，细胞因子水平较低，与同窝小鼠相当。 6小时时，与同窝小鼠相比，LysMcreTNFfl/fl小鼠缺血皮质中产生TNF的小胶质细胞减少了56%，但没有检测到TNF+白细胞。 24 小时时，尽管浸润白细胞群相当，但 LysMcreTNFfl/fl 小鼠的促炎细胞因子（TNF、IL-1β、IL-6、IL-5 和 CXCL1）水平显着降低。我们的结果表明，小胶质细胞 TNF 在急性期具有有益的神经保护作用，并且在实验性缺血后的后期时间点作为神经炎症的调节剂，这可能有助于再生恢复。
Microglia are activated following cerebral ischemia and increase their production of the neuro- and immunomodulatory cytokine tumor necrosis factor (TNF). To address the function of TNF from this cellular source in focal cerebral ischemia we used TNF conditional knock out mice (LysMcreTNFfl/fl) in which the TNF gene was deleted in cells of the myeloid lineage, including microglia. The deletion reduced secreted TNF levels in lipopolysaccharide-stimulated cultured primary microglia by ~93%. Furthermore, phosphorylated-ERK/ERK ratios were significantly decreased in naïve LysMcreTNFfl/fl mice demonstrating altered ERK signal transduction. Micro-PET using 18[F]-fluorodeoxyglucose immediately after focal cerebral ischemia showed increased glucose uptake in LysMcreTNFfl/fl mice, representing significant metabolic changes, that translated into increased infarct volumes at 24 hours and 5 days compared to littermates (TNFfl/fl). In naïve LysMcreTNFfl/fl mice cytokine levels were low and comparable to littermates. At 6 hours, TNF producing microglia were reduced by 56% in the ischemic cortex in LysMcreTNFfl/fl mice compared to littermate mice, whereas no TNF+ leukocytes were detected. At 24 hours, pro-inflammatory cytokine (TNF, IL-1β, IL-6, IL-5 and CXCL1) levels were significantly lower in LysMcreTNFfl/fl mice, despite comparable infiltrating leukocyte populations. Our results identify microglial TNF as beneficial and neuroprotective in the acute phase and as a modulator of neuroinflammation at later time points after experimental ischemia, which may contribute to regenerative recovery.