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-cre^ER+/−tdTomato^St/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.

病毒性脑炎是引起癫痫发作，癫痫和海马损害并伴有认知障碍的主要危险因素，明显降低了幸存者的生活质量。病毒性脑炎发作期间和之后发作和海马神经退行性变的潜在机制尚不完全清楚，这阻碍了预防性治疗的发展。最近的研究结果表明，脑部血源性单核细胞的入侵可能与癫痫发作和脑损伤对脑炎的反应密切相关，而小胶质细胞（大脑的固有免疫细胞）在这些过程中的相对作用尚不清楚。CCR2和CX3CR1是两个趋化因子受体，可调节炎症过程中髓样细胞（如单核细胞和小胶质细胞）的反应。我们使用了Ccr2-CKO和Cx3cr1- KO小鼠使用C57BL / 6小鼠脑炎的泰勒病毒模型，了解这些受体在病毒性脑炎相关的癫痫发作和神经退行性病变中的作用。我们的结果表明，CCR2和CX3CR1在感染中枢神经系统中髓样细胞的积累和海马髓样细胞的活化中起关键作用。此外，通过使用Cx3cr1 -cre ^{ER +/-} tdTomato ^{St / Wt}记者老鼠，我们显示，关于CD45和CD11b的表达，在CNS感染过程中，某些小胶质细胞与单核细胞变得难以区分。有趣的是，CCR2或CX3CR1受体的缺乏与海马损伤的几乎完全预防有关，但并不能阻止病毒中枢神经系统感染后癫痫发作的发展。这些数据与这样的假说相符，即除了浸润的髓样细胞外，中枢神经系统的炎症机制还引发了病毒性脑炎期间癫痫发作的发展。