Targeted deletions of complement lectin pathway genes improve outcome in traumatic brain injury, with MASP-2 playing a major role.
Targeted deletions of complement lectin pathway genes improve outcome in traumatic brain injury, with MASP-2 playing a major role.
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DOI：
10.1186/s40478-020-01041-1
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发表时间：
2020-10-28
影响因子：
7.1
通讯作者：
De Simoni MG
中科院分区：
文献类型：
--
作者：
Mercurio D;Oggioni M;Fumagalli S;Lynch NJ;Roscher S;Minuta D;Perego C;Ippati S;Wallis R;Schwaeble WJ;De Simoni MG
补体激活的凝集素途径（LP）被认为有助于脑炎症。该研究旨在确定LP的关键组分作为可能的新型药理学靶点，有助于TBI结局。我们比较了长期的神经功能缺损和神经病理学的野生型小鼠（WT）的小鼠携带基因缺失的关键LP组件后，实验性TBI。使用WT或MASP-2（Masp 2 −/−）、纤维胶凝蛋白-A（Fcna−/−）、CL-11（Colec 11 −/−）、MASP-1/3（Masp 1 −/−）、MBL-C（Mbl 2 −/−）、MBL-A（Mbl 1 −/−）或MBL−/−（Mbl 1 −/−/Mbl 2 −/−）缺陷型雄性C57 BL/6 J小鼠。小鼠接受假手术或通过控制皮质撞击的TBI。通过神经评分和平衡木步行试验每周评估感觉运动反应，持续4周。为了获得功能结果的比较分析，根据感觉运动性能计算的健康评分对每个转基因系进行评级。对于选定的基因型，在损伤后6周收获脑用于组织病理学分析。与WT相比，MASP-2−/−、MBL−/−和FCN-A−/−小鼠的结局评分更好。其中，MASP-2−/−小鼠在TBI后恢复最好，表现出减少的感觉运动缺陷（3周时减少33%，4周时减少36%）。他们还显示出更高的神经元密度在病变皮层与WT相比增加了31.5%。使用C4 b沉积测定法测量来自MASP-2−/−小鼠的血浆中的LP功能活性揭示了LP功能活性的缺失。LP对TBI后的创伤后炎性病理学有重要贡献，通过不存在LP关键酶MASP-2实现了最高程度的保护，强调了MASP-2靶向TBI的治疗效用。
The lectin pathway (LP) of complement activation is believed to contribute to brain inflammation. The study aims to identify the key components of the LP contributing to TBI outcome as possible novel pharmacological targets. We compared the long-term neurological deficits and neuropathology of wild-type mice (WT) to that of mice carrying gene deletions of key LP components after experimental TBI. WT or MASP-2 (Masp2−/−), ficolin-A (Fcna−/−), CL-11 (Colec11−/−), MASP-1/3 (Masp1−/−), MBL-C (Mbl2−/−), MBL-A (Mbl1−/−) or MBL−/− (Mbl1−/−/Mbl2−/−) deficient male C57BL/6J mice were used. Mice underwent sham surgery or TBI by controlled cortical impact. The sensorimotor response was evaluated by neuroscore and beam walk tests weekly for 4 weeks. To obtain a comparative analysis of the functional outcome each transgenic line was rated according to a health score calculated on sensorimotor performance. For selected genotypes, brains were harvested 6 weeks after injury for histopathological analysis. MASP-2−/−, MBL−/− and FCN-A−/− mice had better outcome scores compared to WT. Of these, MASP-2−/− mice had the best recovery after TBI, showing reduced sensorimotor deficits (by 33% at 3 weeks and by 36% at 4 weeks). They also showed higher neuronal density in the lesioned cortex with a 31.5% increase compared to WT. Measurement of LP functional activity in plasma from MASP-2−/− mice revealed the absence of LP functional activity using a C4b deposition assay. The LP critically contributes to the post-traumatic inflammatory pathology following TBI with the highest degree of protection achieved through the absence of the LP key enzyme MASP-2, underlining a therapeutic utility of MASP-2 targeting in TBI.
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影响因子：
4.2
作者：
Bellander, BM;Singhrao, SK;Svensson, M
通讯作者：
Svensson, M
影响因子：
5.3
作者：
Alawieh, Ali;Langley, E. Farris;Tomlinson, Stephen
通讯作者：
Tomlinson, Stephen
影响因子：
4.4
作者：
Lynch, NJ;Khan, SUH;Schwaeble, WJ
通讯作者：
Schwaeble, WJ
影响因子：
6.7
作者：
Ali YM;Lynch NJ;Haleem KS;Fujita T;Endo Y;Hansen S;Holmskov U;Takahashi K;Stahl GL;Dudler T;Girija UV;Wallis R;Kadioglu A;Stover CM;Andrew PW;Schwaeble WJ
通讯作者：
Schwaeble WJ
影响因子：
6.1
作者：
Bodnar CN;Morganti JM;Bachstetter AD
通讯作者：
Bachstetter AD