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条件性敲除髓系 TNF 可增加小鼠实验性中风后的病灶体积，可能通过改变 ERK1/2 信号通路。

Conditional ablation of myeloid TNF increases lesion volume after experimental stroke in mice, possibly via altered ERK1/2 signaling.

机构信息

Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21st, DK-5000 Odense C, Denmark.

Rigshospitalet, Department of Diagnostics, Molecular Sleep Lab, Nordre Ringvej 69, DK-2600 Glostrup, Denmark.

出版信息

Sci Rep. 2016 Jul 7;6:29291. doi: 10.1038/srep29291.

DOI:10.1038/srep29291
PMID:27384243
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4935869/
Abstract

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 (LysMcreTNF(fl/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 LysMcreTNF(fl/fl) mice demonstrating altered ERK signal transduction. Micro-PET using (18)[F]-fluorodeoxyglucose immediately after focal cerebral ischemia showed increased glucose uptake in LysMcreTNF(fl/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 LysMcreTNF(fl/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 LysMcreTNF(fl/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 LysMcreTNF(fl/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.

摘要

小胶质细胞在脑缺血后被激活，并增加其神经和免疫调节细胞因子肿瘤坏死因子 (TNF) 的产生。为了研究来自这种细胞来源的 TNF 在局灶性脑缺血中的功能，我们使用了 TNF 条件性敲除小鼠 (LysMcreTNF(fl/fl))，其中 TNF 基因在包括小胶质细胞在内的髓系细胞中被删除。该缺失使 LPS 刺激的培养原代小胶质细胞中分泌的 TNF 水平降低了约 93%。此外，在未处理的 LysMcreTNF(fl/fl) 小鼠中，磷酸化 ERK/ERK 比值显著降低，表明 ERK 信号转导发生改变。使用 (18)[F]-氟脱氧葡萄糖进行微 PET 检测，在局灶性脑缺血后立即显示 LysMcreTNF(fl/fl) 小鼠的葡萄糖摄取增加，代表代谢发生了显著变化，与同窝小鼠相比，24 小时和 5 天后梗死体积增加。在未处理的 LysMcreTNF(fl/fl) 小鼠中，细胞因子水平较低且与同窝小鼠相当。在 6 小时时，与同窝小鼠相比，LysMcreTNF(fl/fl) 小鼠缺血皮质中 TNF 产生的小胶质细胞减少了 56%，而未检测到 TNF(+)白细胞。在 24 小时时，LysMcreTNF(fl/fl) 小鼠中促炎细胞因子 (TNF、IL-1β、IL-6、IL-5 和 CXCL1) 水平显著降低，尽管浸润的白细胞群相似。我们的结果表明，小胶质细胞 TNF 在急性阶段是有益和神经保护的，并且在实验性缺血后后期是神经炎症的调节剂，这可能有助于再生恢复。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31ff/4935869/b0f0ee6e9588/srep29291-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31ff/4935869/a63dec9bf486/srep29291-f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31ff/4935869/d295e8851a14/srep29291-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31ff/4935869/d0dbb1745e5e/srep29291-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31ff/4935869/52b394a22acb/srep29291-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31ff/4935869/b0f0ee6e9588/srep29291-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31ff/4935869/a63dec9bf486/srep29291-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31ff/4935869/0e75ec00c1b9/srep29291-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31ff/4935869/c226afc7fed4/srep29291-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31ff/4935869/d295e8851a14/srep29291-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31ff/4935869/d0dbb1745e5e/srep29291-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31ff/4935869/52b394a22acb/srep29291-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31ff/4935869/b0f0ee6e9588/srep29291-f7.jpg

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