Genetic deletion of galectin-3 enhances neuroinflammation, affects microglial activation and contributes to sub-chronic injury in experimental neonatal focal stroke
Genetic deletion of galectin-3 enhances neuroinflammation, affects microglial activation and contributes to sub-chronic injury in experimental neonatal focal stroke
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半乳糖凝集素 3 的基因缺失会增强神经炎症，影响小胶质细胞活化，并导致实验性新生儿局灶性中风的亚慢性损伤
DOI：
10.1016/j.bbi.2016.11.005
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发表时间：
2017-02-01
影响因子：
15.1
通讯作者：
Vexler, Zinaida S.
中科院分区：
文献类型：
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作者：
Chip, Sophorn;Fernandez-Lopez, David;Vexler, Zinaida S.
新生儿卒中和成人卒中的病理生理学在许多方面是不同的，包括炎症反应。我们以前曾发现小胶质细胞在急性新生儿中风中具有内源性保护功能。我们询问半乳糖凝集素-3（Gal 3），一种介导小胶质细胞/巨噬细胞和细胞外基质（ECM）之间相互作用的多效性分子，是否在出生后9-10天小鼠短暂性大脑中动脉闭塞（tMCAO）后的早期损伤中发挥作用。与野生型（WT）幼崽相比，Gal 3敲除幼崽的损伤更严重，细胞因子/趋化因子产生改变，包括MIP 1 α的进一步增加。和MIP 1 β水平和降低的IL 6水平。通过多色流式细胞术测定，Gal 3的缺乏不影响小胶质细胞的形态转化或增殖，但明显减弱损伤后CD 11b（+）/CD 45（中高）细胞的积聚。tMCAO增加WT小鼠或Gal 3-/-小鼠损伤区域内CD 11b（+）/CD 45（低）小胶质细胞和非单核细胞谱系细胞（CD 11b（-）/CD 45（-））中α V和β 3整合素亚单位的表达，但不增加CD 11b（+）/CD 45（中高）细胞中α V和β 3整合素亚单位的表达。α V在CD 68（+）细胞占据和未占据的区域中上调，最显著的是在ECM中，内衬血管，Gal 3-/-小鼠中α V覆盖范围扩大。累积起来，这些数据显示，缺乏Gal 3会导致新生儿局灶性中风后的亚慢性损伤，这可能是通过改变神经炎症环境，包括促炎分子和抗炎分子之间的失衡、对小胶质细胞活化的影响以及ECM组成的失调。(C)2016 Elsevier Inc. All rights reserved.
The pathophysiology of neonatal stroke and adult stroke are distinct in many aspects, including the inflammatory response. We previously showed endogenously protective functions of microglial cells in acute neonatal stroke. We asked if galectin-3 (Gal3), a pleotropic molecule that mediates interactions between microglia/macrophages and the extracellular matrix (ECM), plays a role in early injury after transient middle cerebral occlusion (tMCAO) in postnatal day 9-10 mice. Compared to wild type (WT) pups, in Gal3 knockout pups injury was worse and cytokine/chemokine production altered, including further increase of MIP1 alpha. and MIP1 beta levels and reduced IL6 levels 72 h after tMCAO. Lack of Gal3 did not affect morphological transformation or proliferation of microglia but markedly attenuated accumulation of CD11b(+)/CD45(med-high) cells after injury, as determined by multi-color flow cytometry. tMCAO increased expression of alpha V and beta(3) integrin subunits in CD11b(+)/CD45(low) microglial cells and cells of non-monocyte lineage (CD11b(-)/CD45(-)), but not in CD11b(+)/CD45(med-high) cells within injured regions of WT mice or Gal3-/- mice. alpha V upregulated in areas occupied and not occupied by CD68(+) cells, most prominently in the ECM, lining blood vessels, with expanded alpha V coverage in Gal3-/- mice. Cumulatively, these data show that lack of Gal3 worsens subchronic injury after neonatal focal stroke, likely by altering the neuroinflammatory milieu, including an imbalance between pro- and anti-inflammatory molecules, effects on microglial activation, and deregulation of the composition of the ECM. (C) 2016 Elsevier Inc. All rights reserved.