Scheiblich Hannah, Bicker Gerd
Division of Cell Biology, University of Veterinary Medicine Hannover, Hannover, Germany.
Center for Systems Neuroscience Hannover, Hannover, Germany.
Dev Neurobiol. 2015 Aug;75(8):854-76. doi: 10.1002/dneu.22253. Epub 2014 Dec 6.
Clearance of infected and apoptotic neuronal corpses during inflammatory conditions is a fundamental process to create a favorable environment for neuronal recovery. Microglia are the resident immune cells and the predominant phagocytic cells of the CNS, showing a multitude of cellular responses upon activation. Here, we investigated in functional assays how the CO generating enzyme heme oxygenase 1 (HO-1) influences BV-2 microglial migration, clearance of debris, and neurite outgrowth of human NT2 neurons. Stimulation of HO-1 activity attenuated microglial migration in a scratch wound assay, and phagocytosis in a cell culture model of acute inflammation comprising lipopolysaccharide (LPS)-activated microglia and apoptosis-induced neurons. Application of a CO donor prevented the production of NO during LPS stimulation, and reduced microglial migration and engulfment of neuronal debris. LPS-activated microglia inhibited neurite elongation of human neurons without requiring direct cell-cell surface contact. The inhibition of neurite outgrowth was totally reversed by application of exogenous CO or increased internal CO production through supply of the substrate hemin to HO. Our results point towards a vital cytoprotective role of HO-1/CO signaling after microglial activation. In addition, they support a therapeutic potential of CO releasing chemical agents in the treatment of excessive inflammatory conditions in the CNS.
在炎症条件下清除受感染和凋亡的神经元尸体是为神经元恢复创造有利环境的一个基本过程。小胶质细胞是中枢神经系统中的常驻免疫细胞和主要吞噬细胞，激活后会表现出多种细胞反应。在此，我们通过功能试验研究了一氧化碳生成酶血红素加氧酶1（HO-1）如何影响BV-2小胶质细胞迁移、碎片清除以及人NT2神经元的神经突生长。在划痕试验中，刺激HO-1活性可减弱小胶质细胞迁移，在包含脂多糖（LPS）激活的小胶质细胞和凋亡诱导神经元的急性炎症细胞培养模型中可减弱吞噬作用。应用一氧化碳供体可防止LPS刺激期间一氧化氮的产生，并减少小胶质细胞迁移和神经元碎片的吞噬。LPS激活的小胶质细胞抑制人神经元的神经突伸长，且无需直接的细胞-细胞表面接触。通过应用外源性一氧化碳或通过向HO供应底物血红素增加内源性一氧化碳生成，可完全逆转神经突生长的抑制。我们的结果表明HO-1/一氧化碳信号在小胶质细胞激活后具有重要的细胞保护作用。此外，它们支持一氧化碳释放化学剂在治疗中枢神经系统过度炎症状态方面的治疗潜力。
