Bénardais Karelle, Gudi Viktoria, Gai Lijie, Neßler Jasmin, Singh Vikramjeet, Prajeeth Chittappen K, Skripuletz Thomas, Stangel Martin
Department of Neurology, Hannover Medical School, Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
Glia. 2014 Oct;62(10):1659-70. doi: 10.1002/glia.22706. Epub 2014 Jun 7.
Perinatal inflammation causes immediate changes of the blood-brain barrier (BBB) and thus may have different consequences in adult life including an impact on neurological diseases such as demyelinating disorders. In order to determine if such a perinatal insult affects the course of demyelination in adulthood as "second hit," we simulated perinatal bacterial inflammation by systemic administration of lipopolysaccharide (LPS) to either pregnant mice or newborn animals. Demyelination was later induced in adult animals by cuprizone [bis(cyclohexylidenehydrazide)], which causes oligodendrocyte death with subsequent demyelination accompanied by strong microgliosis and astrogliosis. A single LPS injection at embryonic day 13.5 did not have an impact on demyelination in adulthood. In contrast, serial postnatal LPS injections (P0-P8) caused an early delay of myelin removal in the corpus callosum, which was paralleled by reduced numbers of activated microglia. During remyelination, postnatal LPS treatment enhanced early remyelination with a concomitant increase of mature oligodendrocytes. Furthermore, the postnatal LPS challenge impacts the phenotype of microglia since an elevated mRNA expression of microglia related genes such as TREM 2, CD11b, TNF-α, TGF-β1, HGF, FGF-2, and IGF-1 was found in these preconditioned mice during early demyelination. These data demonstrate that postnatal inflammation has long-lasting effects on microglia functions and modifies the course of demyelination and remyelination in adulthood.
围产期炎症会导致血脑屏障（BBB）立即发生变化，因此在成年期可能会产生不同的后果，包括对脱髓鞘疾病等神经疾病产生影响。为了确定这种围产期损伤是否会作为“二次打击”影响成年期的脱髓鞘进程，我们通过向怀孕小鼠或新生动物全身注射脂多糖（LPS）来模拟围产期细菌炎症。随后，成年动物通过铜离子螯合剂[双（环己叉二酰肼）]诱导脱髓鞘，铜离子螯合剂会导致少突胶质细胞死亡，随后发生脱髓鞘，并伴有强烈的小胶质细胞增生和星形胶质细胞增生。在胚胎第13.5天单次注射LPS对成年期的脱髓鞘没有影响。相比之下，出生后连续注射LPS（P0 - P8）导致胼胝体髓鞘清除早期延迟，同时活化小胶质细胞数量减少。在髓鞘再生过程中，出生后LPS治疗促进了早期髓鞘再生，同时成熟少突胶质细胞数量增加。此外，出生后LPS刺激会影响小胶质细胞的表型，因为在早期脱髓鞘过程中，在这些预处理小鼠中发现小胶质细胞相关基因如TREM 2、CD11b、TNF-α、TGF-β1、HGF、FGF-2和IGF-1的mRNA表达升高。这些数据表明，出生后炎症对小胶质细胞功能具有长期影响，并改变成年期脱髓鞘和髓鞘再生的进程。
