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首页> 外文期刊>The European Journal of Neuroscience >Inhibition of tumour necrosis factor-alpha by antisense targeting produces immunophenotypical and morphological changes in injury-activated microglia and macrophages.
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Inhibition of tumour necrosis factor-alpha by antisense targeting produces immunophenotypical and morphological changes in injury-activated microglia and macrophages.

机译：通过反义靶向抑制肿瘤坏死因子-α在损伤激活的小胶质细胞和巨噬细胞中产生免疫表型和形态学变化。

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Abstract Microglia respond in a stereotypical pattern to a diverse array of pathological states. These changes are coupled to morphological and immunophenotypical alterations and the release of a variety of reactive species, trophic factors and cytokines that modify both microglia and their cellular environment. We examined whether a microglial-produced cytokine, tumour necrosis factor-alpha (TNF-alpha), was involved in the maintenance of microglial activation after spinal cord injury by selective inhibition using TNF-alpha antisense deoxyoligonucleotides (ASOs). Microglia and macrophages harvested from 3 d post-contused rat spinal cord were large and rounded (86.3 +/- 9.6%). They were GSA-IB4-positive (GSA-IB4(+)) (Griffonia simplicifolia lectin, microglia specific; 94.8 +/- 5.1%), strongly OX-42 positive (raised against a type 3 complement/integrin receptor, CD11b; 78.9 +/- 9.1%), ED-1 positive (a lysosomal marker shown to correlate well with immune cell activation; 97.2 +/- 2.6%) and IIA positive (antibody recognizes major histocompatibility complex II; 57.2 +/- 5.6%), indicative of fully activated cells, for up to 48 h after plating. These cells also secreted significant amounts of TNF-alpha (up to 436 pg/microg total protein, 16 h). Fluoroscein isothiocyanate-labelled TNF-alpha ASOs (5, 50 and 200 nm) added to the culture medium were taken up very efficiently into the cells (> 90% cells) and significantly reduced TNF-alpha production by up to 92% (26.5 pg/microg total protein, 16 h, 200 nm TNF-alpha ASOs). Furthermore, few of the treated cells at this time were round (5.4 +/- 2.7%), having become predominantly spindle shaped (74.9 +/- 6.3%) or stellate (21.4 +/- 2.7%); immunophenotypically, although all of them remained GSA-IB4 positive (91.6 +/- 6.2%), many were weakly OX-42 positive and few expressed either ED-1 (12.9 +/- 2.5%) or IIA (19.8 +/- 7.4%). Thus, the secretion of TNF-alpha early in spinal cord injury may be involved in autoactivating microglia/macrophages. However, at the peak of microglial activation after injury, the activation state of microglia/macrophages is not stable and this process may still be reversible by blocking TNF-alpha.
机译：摘要小胶质细胞以定型模式对多种病理状态做出反应。这些变化与形态和免疫表型改变以及修饰小胶质细胞及其细胞环境的各种反应性物种，营养因子和细胞因子的释放有关。我们检查了通过使用TNF-α反义脱氧寡核苷酸（ASOs）的选择性抑制，脊髓损伤后小胶质细胞产生的细胞因子，肿瘤坏死因子-α（TNF-alpha）是否参与维持小胶质细胞的活化。挫伤后3 d从大鼠脊髓收获的小胶质细胞和巨噬细胞较大且呈圆形（86.3 +/- 9.6％）。它们是GSA-IB4阳性（GSA-IB4（+））（Griffonia simplicifolia lectin，小胶质细胞特异性; 94.8 +/- 5.1％），强OX-42阳性（针对3型补体/整合素受体CD11b升高; 78.9） +/- 9.1％），ED-1阳性（一种溶酶体标记物，与免疫细胞激活密切相关; 97.2 +/- 2.6％）和IIA阳性（抗体识别主要的组织相容性复合物II; 57.2 +/- 5.6％），在铺板后长达48小时内，表明细胞已完全活化。这些细胞还分泌了大量的TNF-α（16 h，总蛋白高达436 pg / microg）。添加到培养基中的异硫氰酸荧光素标记的TNF-αASO（5、50和200 nm）可以非常有效地吸收到细胞（> 90％细胞）中，并显着降低TNF-α的生成量，最多可减少92％（26.5 pg） /微克总蛋白，16小时，200 nmTNF-αASO）。此外，此时几乎没有处理过的细胞为圆形（5.4 +/- 2.7％），主要变成纺锤形（74.9 +/- 6.3％）或星状（21.4 +/- 2.7％）;免疫表型上，尽管它们都保持GSA-IB4阳性（91.6 +/- 6.2％），但许多都是OX-42弱的，很少表达ED-1（12.9 +/- 2.5％）或IIA（19.8 +/- 7.4）。 ％）。因此，脊髓损伤早期的TNF-α分泌可能与小胶质细胞/巨噬细胞的自激活有关。但是，在损伤后小胶质细胞激活的高峰期，小胶质细胞/巨噬细胞的激活状态不稳定，并且通过阻断TNF-α，该过程可能仍然是可逆的。

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