Remyelination of cytokine- or antibody-demyelinated CNS aggregate cultures is inhibited by macrophage supplementation
Remyelination of cytokine- or antibody-demyelinated CNS aggregate cultures is inhibited by macrophage supplementation
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DOI：
10.1002/glia.10335
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发表时间：
2004-02-01
期刊：
影响因子：
6.2
通讯作者：
Cuzner, ML
中科院分区：
文献类型：
--
作者：
Diemel, LT;Wolswijk, G;Cuzner, ML
CNS聚集体培养物中的再髓鞘化由巨噬细胞富集和脱髓鞘模式决定。尽管髓鞘损失程度相同，但MBP在抗MOG抗体脱髓鞘聚集体中的积累超过对照，而在IFN-γ诱导的脱髓鞘后恢复显著延迟。在抗体处理的培养物中，髓鞘再生与TGF-β 1、FGF-2和PDGF-AA的培养上清液水平的显著增加以及TNF-α的诱导相关。在去除脱髓鞘损伤后立即进行。IFN-γ处理的培养物中的受损恢复，由TGF-β 1的显著减少表示，通过hrTGF-β 1处理逆转。在两种情况下，在加入脱髓鞘剂之前，巨噬细胞补充培养物诱导了更大程度的髓鞘丢失，随后是不完全的髓鞘再生。在抗体处理的培养物中，这两组中髓鞘再生的失败与TNF-α的数倍升高以及PDGF-AA和FGF-2的适度增加有关。相比之下，在没有任何脱髓鞘处理的情况下，向成熟培养物中补充巨噬细胞导致与早髓鞘生长因子和TNF-α谱相关的MBP的积累增强，这与培养期开始时富含巨噬细胞的聚集体中的情况相似。因此，适应性免疫反应的效应元件似乎覆盖了成熟CNS聚集体中的促炎巨噬细胞因子的前髓鞘原性，抵消了髓鞘修复的潜力。(C)2003 Wiley-Liss，Inc.
Remyelination in CNS aggregate cultures is determined both by macrophage enrichment and the mode of demyelination. Despite the same degree of myelin loss, accumulation of MBP in anti-MOG antibody-demyelinated aggregates overtakes that of controls, while recovery is significantly delayed following IFN-gamma-induced demyelination. In antibody-treated cultures, remyelination was associated with a significant increase in culture supernatant levels of TGF-beta1, FGF-2, and PDGF-AA as well as an induction of TNF-alpha. immediately following removal of the demyelinating insult. The impaired recovery in IFN-gamma-treated cultures, denoted by a significant reduction in TGF-beta1, was reversed by treatment with hrTGF-beta1. Macrophage supplementation of the cultures prior to the addition of either demyelinating agent induced a greater degree of myelin loss followed by incomplete remyelination in both cases. This failure to remyelinate was associated in both groups with a several-fold elevation in TNF-alpha and with modest increases in PDGF-AA and FGF-2 in the antibody-treated cultures. In contrast, macrophage supplementation to mature cultures in the absence of any demyelinating treatment resulted in enhanced accumulation of MBP associated with a promyelinative growth factor and TNF-alpha profile similar to that in aggregates enriched with macrophages at the outset of the culture period. Hence, effector elements of the adaptive immune response appear to override promyelinogenic in favor of proinflammatory macrophage factors in mature CNS aggregates, counteracting the potential for myelin repair. (C) 2003 Wiley-Liss, Inc.