Chemokine receptors CCR2 and CX3CR1 regulate viral encephalitis-induced hippocampal damage but not seizures.
Chemokine receptors CCR2 and CX3CR1 regulate viral encephalitis-induced hippocampal damage but not seizures.
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DOI：
10.1073/pnas.1806754115
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发表时间：
2018-09-18
影响因子：
11.1
通讯作者：
Löscher W
中科院分区：
文献类型：
--
作者：
Käufer C;Chhatbar C;Bröer S;Waltl I;Ghita L;Gerhauser I;Kalinke U;Löscher W
病毒性脑炎是一种常见的医疗紧急情况，通常会导致急性癫痫发作和脑损伤，从而降低生活质量，促进癫痫的发展，并可能导致死亡。在病毒性脑炎的急性和慢性后果中，小胶质细胞（脑内固有免疫细胞）的激活与血液免疫细胞（如单核细胞）的入侵的相对作用还不完全清楚。在这里，我们表明，缺乏趋化因子受体CCR 2或CX 3CR 1，调节骨髓细胞，如单核细胞和小胶质细胞的反应，防止海马损伤，但不能在病毒性脑炎的小鼠模型癫痫发作。治疗策略旨在抑制外周免疫细胞在脑炎期间进入大脑，可以减少脑损伤。病毒性脑炎是癫痫发作、癫痫和海马损伤的主要危险因素，伴有相关的认知障碍，显著降低幸存者的生活质量。病毒性脑炎期间和之后癫痫发作和海马神经退行性变的潜在机制尚未完全了解，阻碍了预防性治疗的发展。最近的研究结果表明，血生单核细胞的脑入侵可能是至关重要的参与癫痫发作和脑损伤的脑炎，而小胶质细胞，大脑的居民免疫细胞，在这些过程中的相对作用尚不清楚。CCR 2和CX 3CR 1是两种趋化因子受体，在炎症期间调节骨髓细胞（如单核细胞和小胶质细胞）的反应。我们使用Ccr 2-KO和Cx 3cr 1-KO小鼠来了解这些受体在病毒性脑炎相关癫痫发作和神经变性中的作用，使用C57 BL/6小鼠中的Theiler病毒脑炎模型。我们的研究结果表明，CCR 2以及CX 3CR 1在CNS中髓样细胞的积累和感染后海马髓样细胞的激活中起关键作用。此外，通过使用Cx 3cr 1-creER+/−tdTomatoSt/Wt报告基因小鼠，我们发现，就CD 45和CD 11b表达而言，在CNS感染期间，一些小胶质细胞变得与单核细胞难以区分。有趣的是，CCR 2或CX 3CR 1受体的缺乏与几乎完全预防海马损伤有关，但不能预防病毒CNS感染后癫痫发作的发生。这些数据与病毒性脑炎期间CNS炎症机制而非浸润性髓样细胞触发癫痫发作的假设一致。
Viral encephalitis is a frequent medical emergency, often resulting in acute seizures and brain damage, which reduce quality of life, promote the development of epilepsy, and can cause death. The relative roles of activation of microglia, the brain-resident innate immune cells, versus invasion of blood-borne immune cells such as monocytes in the acute and chronic consequences of viral encephalitis are only incompletely understood. Here we show that lack of the chemokine receptors CCR2 or CX3CR1, which regulate the responses of myeloid cells such as monocytes and microglia, prevents hippocampal damage but not seizures in a mouse model of viral encephalitis. Treatment strategies aimed at inhibiting peripheral immune cells from entering the brain during encephalitis could reduce brain damage. Viral encephalitis is a major risk factor for the development of seizures, epilepsy, and hippocampal damage with associated cognitive impairment, markedly reducing quality of life in survivors. The mechanisms underlying seizures and hippocampal neurodegeneration developing during and after viral encephalitis are only incompletely understood, hampering the development of preventive treatments. Recent findings suggest that brain invasion of blood-born monocytes may be critically involved in both seizures and brain damage in response to encephalitis, whereas the relative role of microglia, the brain’s resident immune cells, in these processes is not clear. CCR2 and CX3CR1 are two chemokine receptors that regulate the responses of myeloid cells, such as monocytes and microglia, during inflammation. We used Ccr2-KO and Cx3cr1-KO mice to understand the role of these receptors in viral encephalitis-associated seizures and neurodegeneration, using the Theiler’s virus model of encephalitis in C57BL/6 mice. Our results show that CCR2 as well as CX3CR1 plays a key role in the accumulation of myeloid cells in the CNS and activation of hippocampal myeloid cells upon infection. Furthermore, by using Cx3cr1-creER+/−tdTomatoSt/Wt reporter mice, we show that, with regard to CD45 and CD11b expression, some microglia become indistinguishable from monocytes during CNS infection. Interestingly, the lack of CCR2 or CX3CR1 receptors was associated with almost complete prevention of hippocampal damage but did not prevent seizure development after viral CNS infection. These data are compatible with the hypothesis that CNS inflammatory mechanism(s) other than the infiltrating myeloid cells trigger the development of seizures during viral encephalitis.
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影响因子：
30.5
作者：
Goldmann T;Wieghofer P;Jordão MJ;Prutek F;Hagemeyer N;Frenzel K;Amann L;Staszewski O;Kierdorf K;Krueger M;Locatelli G;Hochgerner H;Zeiser R;Epelman S;Geissmann F;Priller J;Rossi FM;Bechmann I;Kerschensteiner M;Linnarsson S;Jung S;Prinz M
通讯作者：
Prinz M
影响因子：
5.6
作者：
Aronica E;Bauer S;Bozzi Y;Caleo M;Dingledine R;Gorter JA;Henshall DC;Kaufer D;Koh S;Löscher W;Louboutin JP;Mishto M;Norwood BA;Palma E;Poulter MO;Terrone G;Vezzani A;Kaminski RM
通讯作者：
Kaminski RM
LY6C+“炎症单核细胞”是在西尼罗河病毒脑炎中以致病方式募集的小胶质前体。
DOI：
10.1084/jem.20080421
发表时间：
2008-09-29
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Getts DR;Terry RL;Getts MT;Müller M;Rana S;Shrestha B;Radford J;Van Rooijen N;Campbell IL;King NJ
通讯作者：
King NJ
影响因子：
7.3
作者：
Greter M;Lelios I;Croxford AL
通讯作者：
Croxford AL
影响因子：
5.6
作者：
Klein P;Dingledine R;Aronica E;Bernard C;Blümcke I;Boison D;Brodie MJ;Brooks-Kayal AR;Engel J Jr;Forcelli PA;Hirsch LJ;Kaminski RM;Klitgaard H;Kobow K;Lowenstein DH;Pearl PL;Pitkänen A;Puhakka N;Rogawski MA;Schmidt D;Sillanpää M;Sloviter RS;Steinhäuser C;Vezzani A;Walker MC;Löscher W
通讯作者：
Löscher W