TGFβ receptor II gene deletion in leucocytes prevents cerebral vasculitis in bacterial meningitis
TGFβ receptor II gene deletion in leucocytes prevents cerebral vasculitis in bacterial meningitis
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DOI：
10.1093/brain/awl192
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发表时间：
2006-09-01
期刊：
影响因子：
14.5
通讯作者：
Fontana, Adriano
中科院分区：
文献类型：
--
作者：
Malipiero, Ursula;Koedel, Uwe;Fontana, Adriano
在细菌性脑膜炎中，趋化因子导致多形核白细胞（PMN）募集到CNS中。在蛛网膜下腔的感染部位，PMN释放活性氧、活性氮中间体（RNI）和白细胞介素-1 β（IL-1 β）。虽然这些免疫因子有助于清除细菌，但它们也导致与脑膜炎相关的神经元损伤。转化生长因子β（TGF β）是PMN和巨噬细胞的有效灭活剂，因为TGF β抑制ROI、RNI和IL-1的产生。在这里，我们报告说，删除TGF β受体II基因的PMN增强PMN招聘到中枢神经系统的肺炎链球菌脑膜炎小鼠。这与更有效地清除细菌，几乎完全预防脑内坏死性血管炎有关。感染对照小鼠和缺乏TGF β受体II的小鼠中枢神经系统中中性粒细胞的差异无法通过作用于中性粒细胞的趋化因子表达的改变来解释。相反，TGF β被发现损害L（白细胞）-选择素在对照小鼠的PMN上的表达，而不是从缺乏TGF β受体II的小鼠。已知L-选择素对细菌性脑膜炎中PMN的募集至关重要。我们的结论是，缺陷TGF β信号在中性粒细胞是有益的细菌性脑膜炎，通过改善中性粒细胞的迁移和细菌清除。
In bacterial meningitis, chemokines lead to recruitment of polymorphonuclear leucocytes (PMN) into the CNS. At the site of infection in the subarachnoid space, PMN release reactive oxygen species, reactive nitrogen intermediates (RNI) and interleukin-1 beta (IL-1 beta). Although these immune factors assist in clearance of bacteria, they also result in neuronal injury associated with meningitis. Transforming growth factor beta (TGF beta) is a potent deactivator of PMN and macrophages since TGF beta suppresses the production of ROI, RNI and IL-1. Here, we report that the deletion of the TGF beta receptor II gene in PMN enhances PMN recruitment into the CNS of mice with Streptococcus pneumoniae meningitis. This was associated with more efficient clearance of bacteria, and almost complete prevention of intracerebral necrotizing vasculitis. Differences in PMN in the CNS of infected control mice and mice lacking TGF beta receptor II were not explained by altered expression of chemokines acting on PMN. Instead, TGF beta was found to impair the expression of L (leucocyte)-selectin on PMN from control mice but not from mice lacking TGF beta receptor II. L-Selectin is known to be essential for PMN recruitment in bacterial meningitis. We conclude that defective TGF beta signalling in PMN is beneficial in bacterial meningitis by ameliorating migration of PMN and bacterial clearance.