Systemic inflammation in early neonatal mice induces transient and lasting neurodegenerative effects.
Systemic inflammation in early neonatal mice induces transient and lasting neurodegenerative effects.
复制标题
DOI：
10.1186/s12974-015-0299-3
复制
发表时间：
2015-04-29
影响因子：
9.3
通讯作者：
Brites D
中科院分区：
文献类型：
--
作者：
Cardoso FL;Herz J;Fernandes A;Rocha J;Sepodes B;Brito MA;McGavern DB;Brites D
炎症介质脂多糖（LPS）已被证明可诱导新生小鼠急性神经胶质瘤。然而，在全身性炎症之后的一周内，对小鼠神经发育程序的进行性影响尚不清楚。因此，我们研究了在小鼠出生后第一周重复LPS给药对发育中的中枢神经系统（CNS）的影响，这种情况类似于晚期早产儿的脓毒症。从出生后第4天（PND）至第6天，新生小鼠每天腹腔注射LPS （6 mg/kg）诱导全身炎症。用Luxol快速蓝和甲酚紫分别染色白质和神经元，观察其对神经发育的影响。通过量化基质金属蛋白酶（MMP）、toll样受体(TLR)-4、高迁移率组盒(HMGB)-1和autotaxin （ATX）的表达/活性来评估炎症反应。此外，用B6 CX3CR1gfp/+小鼠联合冷冻免疫荧光测定其对髓鞘形成、小胶质细胞和星形胶质细胞的急性、延迟和持久影响。LPS处理导致急性体重和脑重减轻，以及明显的脑结构改变，如小脑发育不全、神经元丢失/萎缩和髓鞘形成延迟。髓鞘形成受损与LPS处理后早期NG2祖细胞增殖和分化的改变有关，而与中枢神经系统髓样细胞过度吞噬无关。除了大脑结构的破坏外，还观察到对LPS的强烈炎症反应。炎症生物标志物的量化显示，ATX的表达降低，HMGB1、TLR-4和MMP-9的表达水平同时升高。急性星形胶质细胞（GFAP+细胞）在脑实质和微血管界面和实质小胶质细胞（CX3CR1+细胞）也被观察到。这些变化先于CX3CR1+细胞在稍后的时间点在血管周围的迁移/增殖，以及随后GFAP+星形胶质细胞的丧失。总的来说，我们的研究揭示了外周LPS刺激下新生小鼠大脑中复杂的先天炎症反应和相关的结构变化。这些发现可以解释新生儿败血症后出现的一些神经行为异常。
The inflammatory mediator lipopolysaccharide (LPS) has been shown to induce acute gliosis in neonatal mice. However, the progressive effects on the murine neurodevelopmental program over the week that follows systemic inflammation are not known. Thus, we investigated the effects of repeated LPS administration in the first postnatal week in mice, a condition mimicking sepsis in late preterm infants, on the developing central nervous system (CNS). Systemic inflammation was induced by daily intraperitoneal administration (i.p.) of LPS (6 mg/kg) in newborn mice from postnatal day (PND) 4 to PND6. The effects on neurodevelopment were examined by staining the white matter and neurons with Luxol Fast Blue and Cresyl Violet, respectively. The inflammatory response was assessed by quantifying the expression/activity of matrix metalloproteinases (MMP), toll-like receptor (TLR)-4, high mobility group box (HMGB)-1, and autotaxin (ATX). In addition, B6 CX3CR1gfp/+ mice combined with cryo-immunofluorescence were used to determine the acute, delayed, and lasting effects on myelination, microglia, and astrocytes. LPS administration led to acute body and brain weight loss as well as overt structural changes in the brain such as cerebellar hypoplasia, neuronal loss/shrinkage, and delayed myelination. The impaired myelination was associated with alterations in the proliferation and differentiation of NG2 progenitor cells early after LPS administration, rather than with excessive phagocytosis by CNS myeloid cells. In addition to disruptions in brain architecture, a robust inflammatory response to LPS was observed. Quantification of inflammatory biomarkers revealed decreased expression of ATX with concurrent increases in HMGB1, TLR-4, and MMP-9 expression levels. Acute astrogliosis (GFAP+ cells) in the brain parenchyma and at the microvasculature interface together with parenchymal microgliosis (CX3CR1+ cells) were also observed. These changes preceded the migration/proliferation of CX3CR1+ cells around the vessels at later time points and the subsequent loss of GFAP+ astrocytes. Collectively, our study has uncovered a complex innate inflammatory reaction and associated structural changes in the brains of neonatal mice challenged peripherally with LPS. These findings may explain some of the neurobehavioral abnormalities that develop following neonatal sepsis.
登录
查看更多内容
影响因子：
3.7
作者：
Cardoso FL;Kittel A;Veszelka S;Palmela I;Tóth A;Brites D;Deli MA;Brito MA
通讯作者：
Brito MA
影响因子：
15.1
作者：
Erickson, Michelle A.;Banks, William A.
通讯作者：
Banks, William A.
影响因子：
9.3
作者：
Dohgu S;Fleegal-DeMotta MA;Banks WA
通讯作者：
Banks WA
影响因子：
3.8
作者：
Agnello, D;Wang, HC;Ghezzi, P
通讯作者：
Ghezzi, P
影响因子：
15.1
作者：
Bland, Sondra T.;Beckley, Jacob T.;Bilbo, Staci D.
通讯作者：
Bilbo, Staci D.