Takahashi Kazuya, Rochford Christian D P, Neumann Harald
Neuroimmunology Unit, European Neuroscience Institute Göttingen, Germany.
J Exp Med. 2005 Feb 21;201(4):647-57. doi: 10.1084/jem.20041611.
Elimination of apoptotic neurons without inflammation is crucial for brain tissue homeostasis, but the molecular mechanism has not been firmly established. Triggering receptor expressed on myeloid cells-2 (TREM2) is a recently identified innate immune receptor. Here, we show expression of TREM2 in microglia. TREM2 stimulation induced DAP12 phosphorylation, extracellular signal-regulated kinase phosphorylation, and cytoskeleton reorganization and increased phagocytosis. Knockdown of TREM2 in microglia inhibited phagocytosis of apoptotic neurons and increased gene transcription of tumor necrosis factor alpha and nitric oxide synthase-2, whereas overexpression of TREM2 increased phagocytosis and decreased microglial proinflammatory responses. Thus, TREM2 deficiency results in impaired clearance of apoptotic neurons and inflammation that might be responsible for the brain degeneration observed in patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy/Nasu-Hakola disease.
在无炎症的情况下清除凋亡神经元对于脑组织稳态至关重要，但其分子机制尚未完全明确。髓系细胞触发受体2（TREM2）是最近发现的一种天然免疫受体。在此，我们展示了TREM2在小胶质细胞中的表达。TREM2刺激可诱导DAP12磷酸化、细胞外信号调节激酶磷酸化以及细胞骨架重组，并增强吞噬作用。小胶质细胞中TREM2的敲低抑制了凋亡神经元的吞噬作用，并增加了肿瘤坏死因子α和一氧化氮合酶-2的基因转录，而TREM2的过表达则增强了吞噬作用并降低了小胶质细胞的促炎反应。因此，TREM2缺陷导致凋亡神经元清除受损和炎症，这可能是多囊性脂膜性骨发育异常伴硬化性白质脑病/纳苏-哈科拉病患者出现脑退化的原因。
