Prolonged microglial cell activation and lymphocyte infiltration following experimental herpes encephalitis.
Prolonged microglial cell activation and lymphocyte infiltration following experimental herpes encephalitis.
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DOI：
10.4049/jimmunol.181.9.6417
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发表时间：
2008-11-01
期刊：
影响因子：
--
通讯作者：
Lokensgard JR
中科院分区：
文献类型：
--
作者：
Marques CP;Cheeran MC;Palmquist JM;Hu S;Urban SL;Lokensgard JR
实验性鼠HSV-1脑感染刺激小胶质细胞驱动的促炎趋化因子产生，其先于脑浸润性全身免疫细胞的存在。在本研究中，我们研究了白细胞进入HSV感染小鼠脑的表型和浸润动力学。使用实时生物发光成像，荧光素酶（+）-脾细胞，通过尾静脉注射转移到HSV感染的动物的脑中的浸润，随后超过18天的时间过程。在感染后（p.i.）5、8、14和30天对脑浸润性白细胞进行流式细胞术分析，以评估其表型。在感染早期观察到主要的巨噬细胞（CD 45 hiCD 11b + Ly 6Chi）和中性粒细胞（CD 45 hiCD 11b + Ly 6 G+）浸润，TNF- α mRNA表达水平升高。到14 d p.i.，表型特征转变为主要的淋巴细胞（CD 45 hiCD 3+）浸润。这种淋巴细胞浸润直到感染后30天才被检测到，当感染性病毒不能回收时，CD 8+和CD 4 + T细胞分别以3：1的比例存在。这种T淋巴细胞浸润可增加脑中IFN-γ RNA的表达。还检测到驻留小胶质细胞（CD 45 intCD 11b+）的激活，直到感染后30天，如通过MHC II类表达所评估的。活化的小胶质细胞被进一步鉴定为IL-1β的主要来源。此外，感染小鼠在感染后4天给予引发的免疫细胞。死亡率显著上升总之，这些结果表明，鼻内感染导致早期巨噬细胞和中性粒细胞浸润到脑中，随后是延长的小胶质细胞活化和T淋巴细胞滞留。类似的延长的神经免疫激活可能有助于在疱疹性脑炎患者中观察到的神经病理学后遗症。
Experimental murine HSV-1 brain infection stimulates microglial cell-driven pro-inflammatory chemokine production which precedes the presence of brain-infiltrating systemic immune cells. In the present study, we investigated the phenotypes and infiltration kinetics of leukocyte trafficking into HSV-infected murine brains. Using real-time bioluminescence imaging, the infiltration of luciferase(+)-splenocytes, transferred via tail-vein injection, into the brains of HSV-infected animals was followed over an 18 d time-course. Flowcytometric analysis of brain-infiltrating leukocytes at 5, 8, 14, and 30 d post-infection (p.i.), was performed to assess their phenotype. A predominantly macrophage (CD45hiCD11b+Ly6Chi) and neutrophil (CD45hiCD11b+Ly6G+) infiltration was seen early during infection, with elevated levels of TNF- α mRNA expression. By 14 d p.i., the phenotypic profile shifted to a predominantly lymphocytic (CD45hiCD3+) infiltrate. This lymphocyte infiltrate was detected until 30 d p.i., when infectious virus could not be recovered, with CD8+ and CD4+ T-cells present at a 3:1 ratio respectively. This T lymphocyte infiltration paralleled increased IFN-γ RNA expression in the brain. Activation of resident microglia (CD45intCD11b+) was also detected until 30 d p.i., as assessed by MHC class II expression. Activated microglial cells were further identified as the predominant source of IL-1β. In addition, infected mice given primed immunocytes at 4 d p.i. showed a significant increase in mortality. Taken together, these results demonstrate that intranasal infection results in early macrophage and neutrophil infiltration into the brain followed by prolonged microglial activation and T lymphocyte retention. Similar prolonged neuroimmune activation may contribute to the neuropathological sequelae observed in herpes encephalitis patients.
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