CXC chemokine receptor-2 ligands are required for neutrophil-mediated host defense in experimental brain abscesses
CXC chemokine receptor-2 ligands are required for neutrophil-mediated host defense in experimental brain abscesses
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DOI：
10.4049/jimmunol.166.7.4634
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发表时间：
2001-04-01
影响因子：
4.4
通讯作者：
Hickey, WF
中科院分区：
文献类型：
--
作者：
Kielian, T;Barry, B;Hickey, WF
我们利用人类脑脓肿的主要病原之一金黄色葡萄球菌建立了小鼠脑脓肿模型。在金黄色葡萄球菌暴露后24小时至7天内观察到血脑屏障的直接损害，这可以通过在脑实质中积累血清IgG来证明。脑脓肿的免疫组织化学和流式细胞术显示有明显的中性粒细胞浸润。为了解决中性粒细胞在早期遏制金黄色葡萄球菌感染中的重要性，在植入细菌载珠之前，小鼠暂时耗尽中性粒细胞。与对照动物相比，中性粒细胞减少的动物一贯表现出更严重的脑脓肿和更高的中枢神经系统细菌负担。金黄色葡萄球菌在接触细菌后6小时内诱导大量脑内趋化因子，包括巨噬细胞炎性蛋白(MIP)-1 α /CCL3、MIP-1 β /CCL4、MIP-2/CXCL1、单核细胞趋化蛋白-1/CCL2和TCA-3/ CCL1。这些趋化因子也在新生小鼠小胶质细胞和星形胶质细胞暴露于体外热灭活金黄色葡萄球菌的原代培养物中表达。由于中性粒细胞在早期脑脓肿发展过程中构成了大部分细胞浸润，因此随后的分析集中在MIP-2和KC/CXCL1这两种吸引中性粒细胞的CXC趋化因子上。金黄色葡萄球菌暴露后，大脑中MIP-2和KC蛋白水平均显著升高。在CXCR2基因敲除小鼠中，中性粒细胞向脑实质外渗受损，并与细菌负荷增加有关。这些研究证明了CXCR2配体MIP-2、KC和中性粒细胞在脑内对金黄色葡萄球菌的急性宿主反应中的重要性。
We have developed a mouse brain abscess model by using Staphylococcus aureus, one of the main etiologic agents of brain abscesses in humans. Direct damage to the blood-brain barrier was observed from 24 h to 7 days after S. aureus exposure as demonstrated by the accumulation of serum IgG in the brain parenchyma. Evaluation of brain abscesses by immunohistochemistry and flow cytometry revealed a prominent neutrophil infiltrate. To address the importance of neutrophils in the early containment of S. aureus infection in the brain, mice were transiently depleted of neutrophils before implantation of bacteria-laden beads. Neutrophil-depleted animals consistently demonstrated more severe brain abscesses and higher CNS bacterial burdens compared with control animals. S. aureus led to the induction of numerous chemokines in the brain, including macrophage-inflammatory protein (MIP)-1 alpha /CCL3, MIP-1 beta /CCL4, MIP-2/CXCL1, monocyte chemoattractant protein-1/CCL2, and TCA-3/ CCL1, within 6 h after bacterial exposure. These chemokines also were expressed by both primary cultures of neonatal mouse microglia and astrocytes exposed to heat-inactivated S. aureus in vitro. Because neutrophils constitute the majority of the cellular infiltrate in early brain abscess development, subsequent analysis focused on MIP-2 and KC/CXCL1, two neutrophil-attracting CXC chemokines. Both MIP-2 and KC protein levels were significantly elevated in the brain after S. aureus exposure. Neutrophil extravasation into the brain parenchyma was impaired in CXCR2 knockout mice and was associated with increased bacterial burdens. These studies demonstrate the importance of the CXCR2 ligands MIP-2 and KC and neutrophils in the acute host response to S. aureus in the brain.