CD14 is a key organizer of microglial responses to CNS infection and injury
CD14 is a key organizer of microglial responses to CNS infection and injury
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DOI：
10.1002/glia.22955
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发表时间：
2016-04-01
期刊：
影响因子：
6.2
通讯作者：
Hanisch, Uwe-Karsten
中科院分区：
文献类型：
--
作者：
Janova, Hana;Boettcher, Chotima;Hanisch, Uwe-Karsten
小胶质细胞，中枢神经系统的先天免疫细胞，通过重叠的受体集感知感染和损伤。Toll样受体（TLR）4识别细菌脂多糖（LPS）和多种损伤相关因子。我们发现，其辅助受体CD14在小胶质细胞中具有三种非冗余功能。首先，与外周巨噬细胞相比，它赋予高达100倍的LPS敏感性，以实现有效的促炎细胞因子诱导。其次，CD14通过干扰素介导的反馈防止对大量LPS攻击的过度应答。第三，CD14对于小胶质细胞对组织损伤相关信号的反应是必需的。在小鼠中，这些功能对于平衡CNS对细菌感染、创伤性和缺血性损伤的反应至关重要，因为CD14缺乏会导致炎症减轻或过度、免疫细胞募集不足或过度或卒中结局恶化。虽然CD14协调TLR4和相关免疫受体的功能，但它本身受TLR和非TLR系统的调节，从而在感染性和非感染性CNS挑战时微调小胶质细胞损伤感应能力。
Microglia, innate immune cells of the CNS, sense infection and damage through overlapping receptor sets. Toll-like receptor (TLR) 4 recognizes bacterial lipopolysaccharide (LPS) and multiple injury-associated factors. We show that its co-receptor CD14 serves three non-redundant functions in microglia. First, it confers an up to 100-fold higher LPS sensitivity compared to peripheral macrophages to enable efficient proinflammatory cytokine induction. Second, CD14 prevents excessive responses to massive LPS challenges via an interferon -mediated feedback. Third, CD14 is mandatory for microglial reactions to tissue damage-associated signals. In mice, these functions are essential for balanced CNS responses to bacterial infection, traumatic and ischemic injuries, since CD14 deficiency causes either hypo- or hyperinflammation, insufficient or exaggerated immune cell recruitment or worsened stroke outcomes. While CD14 orchestrates functions of TLR4 and related immune receptors, it is itself regulated by TLR and non-TLR systems to thereby fine-tune microglial damage-sensing capacity upon infectious and non-infectious CNS challenges.