Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation.
Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation.
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DOI：
10.1038/ncomms2230
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发表时间：
2012
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
血脑屏障破坏、小胶质细胞激活和神经变性是多发性硬化症的特征。然而，激活先天免疫反应的最初触发因素及其在轴突损伤中的作用尚不清楚。在这里，我们表明，血液蛋白纤维蛋白原诱导对血管系统的快速小胶质反应，是神经炎症中的轴突损伤所必需的。利用体内双光子显微镜，我们证明了在髓鞘丢失或瘫痪发生之前，小胶质细胞就形成了血管周围簇，在血浆蛋白中，纤维蛋白原在体内特异性地诱导快速和持续的小胶质细胞反应。纤维蛋白原渗漏与轴突损伤面积相关，并诱导小胶质细胞释放活性氧。用抗凝治疗阻断纤维蛋白形成或从基因上消除小胶质细胞整合素受体CD11b/CD18识别的纤维蛋白原结合基序可以抑制血管周围小胶质细胞聚集和轴突损伤。因此，血脑屏障破坏时纤维蛋白原渗漏引发的血管周围小胶质细胞的早期和进行性聚集导致神经炎性疾病中的轴突损伤。多发性硬化症的特征是小胶质细胞的激活。达瓦洛斯等人。研究小鼠神经炎症的早期阶段，发现血浆蛋白纤维蛋白原诱导脑血管周围的小胶质细胞聚集，从而促进病变形成和局灶性轴突损伤。
Blood-brain barrier disruption, microglial activation and neurodegeneration are hallmarks of multiple sclerosis. However, the initial triggers that activate innate immune responses and their role in axonal damage remain unknown. Here we show that the blood protein fibrinogen induces rapid microglial responses toward the vasculature and is required for axonal damage in neuroinflammation. Using in vivo two-photon microscopy, we demonstrate that microglia form perivascular clusters before myelin loss or paralysis onset and that, of the plasma proteins, fibrinogen specifically induces rapid and sustained microglial responses in vivo. Fibrinogen leakage correlates with areas of axonal damage and induces reactive oxygen species release in microglia. Blocking fibrin formation with anticoagulant treatment or genetically eliminating the fibrinogen binding motif recognized by the microglial integrin receptor CD11b/CD18 inhibits perivascular microglial clustering and axonal damage. Thus, early and progressive perivascular microglial clustering triggered by fibrinogen leakage upon blood-brain barrier disruption contributes to axonal damage in neuroinflammatory disease. Multiple sclerosis is characterized by the activation of microglia cells. Davalos et al. investigate the early stages of neuroinflammation in mice and reveal that the plasma protein fibrinogen induces microglial clustering around the brain vasculature, which facilitates lesion formation and focal axonal damage.
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影响因子：
20.3
作者：
Dichmann, S;Idzko, M;Norgauer, J
通讯作者：
Norgauer, J
影响因子：
64.5
作者：
Bugge, TH;Kombrinck, KW;Degen, JL
通讯作者：
Degen, JL
影响因子：
5.3
作者：
Jung, S;Aliberti, J;Littman, DR
通讯作者：
Littman, DR
DOI：
10.1084/jem.20092749
发表时间：
2010-08-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hao J;Liu R;Piao W;Zhou Q;Vollmer TL;Campagnolo DI;Xiang R;La Cava A;Van Kaer L;Shi FD
通讯作者：
Shi FD
影响因子：
25
作者：
Denise, A;Garcia, R;Sofroniew, MV
通讯作者：
Sofroniew, MV