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可溶性肿瘤坏死因子的基因消融不影响小鼠中度脊髓损伤后的损伤大小和功能恢复。

Genetic Ablation of Soluble TNF Does Not Affect Lesion Size and Functional Recovery after Moderate Spinal Cord Injury in Mice.

作者信息

Ellman Ditte Gry, Degn Matilda, Lund Minna Christiansen, Clausen Bettina Hjelm, Novrup Hans Gram, Flæng Simon Bertram, Jørgensen Louise Helskov, Suntharalingam Lujitha, Svenningsen Åsa Fex, Brambilla Roberta, Lambertsen Kate Lykke

机构信息

Neurobiology Research, Institute of Molecular Medicine, J.B. Winsloewsvej 21, st, 5000 Odense C, Denmark.

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

出版信息

Mediators Inflamm. 2016;2016:2684098. doi: 10.1155/2016/2684098. Epub 2016 Dec 14.

DOI:10.1155/2016/2684098
PMID:28070141
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5192339/
Abstract

Traumatic spinal cord injury (SCI) is followed by an instant increase in expression of the microglial-derived proinflammatory cytokine tumor necrosis factor (TNF) within the lesioned cord. TNF exists both as membrane-anchored TNF (mTNF) and as cleaved soluble TNF (solTNF). We previously demonstrated that epidural administration of a dominant-negative inhibitor of solTNF, XPro1595, to the contused spinal cord resulted in changes in Iba1 protein expression in microglia/macrophages, decreased lesion volume, and improved locomotor function. Here, we extend our studies using mice expressing mTNF, but no solTNF (mTNF), to study the effect of genetic ablation of solTNF on SCI. We demonstrate that TNF levels were significantly decreased within the lesioned spinal cord 3 days after SCI in mTNF mice compared to littermates. This decrease did, however, not translate into significant changes in other pro- and anti-inflammatory cytokines (IL-10, IL-1, IL-6, IL-5, IL-2, CXCL1, CCL2, or CCL5), despite a tendency towards increased IL-10 and decreased IL-1, TNFR1, and TNFR2 levels in mTNF mice. In addition, microglial and leukocyte infiltration, activation state (Iba1, CD11b, CD11c, CD45, and MHCII), lesion size, and functional outcome after moderate SCI were comparable between genotypes. Collectively, our data demonstrate that genetic ablation of solTNF does not significantly modulate postlesion outcome after SCI.

摘要

创伤性脊髓损伤（SCI）后，损伤脊髓内小胶质细胞衍生的促炎细胞因子肿瘤坏死因子（TNF）的表达会立即增加。TNF 以膜锚定 TNF（mTNF）和裂解的可溶性 TNF（solTNF）两种形式存在。我们之前证明，向挫伤的脊髓硬膜外给予 solTNF 的显性负性抑制剂 XPro1595，会导致小胶质细胞/巨噬细胞中 Iba1 蛋白表达发生变化，减小损伤体积，并改善运动功能。在此，我们使用表达 mTNF 但不表达 solTNF（mTNF）的小鼠扩展我们的研究，以研究 solTNF 的基因敲除对 SCI 的影响。我们证明，与同窝小鼠相比，mTNF 小鼠在 SCI 后 3 天损伤脊髓内的 TNF 水平显著降低。然而，尽管 mTNF 小鼠中 IL-10 有增加趋势，IL-1、TNFR1 和 TNFR2 水平有降低趋势，但这种降低并未转化为其他促炎和抗炎细胞因子（IL-10、IL-1、IL-6、IL-5、IL-2、CXCL1、CCL2 或 CCL5）的显著变化。此外，在中度 SCI 后，不同基因型之间的小胶质细胞和白细胞浸润、激活状态（Iba1、CD11b、CD11c、CD45 和 MHCII）、损伤大小和功能结果相当。总体而言，我们的数据表明，solTNF 的基因敲除不会显著调节 SCI 后的损伤后结果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b700/5192339/2c66766f03ff/MI2016-2684098.006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b700/5192339/b224b0c5edbf/MI2016-2684098.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b700/5192339/117241e62a0f/MI2016-2684098.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b700/5192339/7ba360973a61/MI2016-2684098.003.jpg
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