Exacerbation of experimental autoimmune encephalomyelitis in ceramide synthase 6 knockout mice is associated with enhanced activation/migration of neutrophils
Exacerbation of experimental autoimmune encephalomyelitis in ceramide synthase 6 knockout mice is associated with enhanced activation/migration of neutrophils
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DOI：
10.1038/icb.2015.47
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发表时间：
2015-10-01
影响因子：
4
通讯作者：
Schiffmann, Susanne
中科院分区：
文献类型：
--
作者：
Eberle, Max;Ebel, Philipp;Schiffmann, Susanne
神经酰胺是炎症过程的介质。在实验性自身免疫性脑脊髓炎 (EAE)（一种多发性硬化症 (MS) 动物模型）中，我们观察到在 EAE 症状出现之前，外周血白细胞中的 CerS6 mRNA 表达上调了 15 倍。在 MS 患者的外周血白细胞中，发现了 3.9 倍的上调。 CerS6 的完全基因缺失和外周血白细胞中 CerS6 的选择性缺失加剧了 EAE 小鼠临床症状的进展。这与 EAE 小鼠腰脊髓白细胞（主要是中性粒细胞浸润）增强和脱髓鞘增强有关。干扰素-γ/肿瘤坏死因子α（IFN-γ/TNF-α）和粒细胞集落刺激因子（G-CSF）均驱动EAE的发展并诱导整合素CD11b和趋化因子受体C-X-C基序趋化因子受体2（CXCR2）的表达，我们发现它们还诱导CerS6表达。在体内，CerS6 的基因缺失增强了中性粒细胞的激活/迁移，CD11b 和 CXCR2 上调的增强反映了这一点。在体外，CerS6 的基因缺失增强了 IFN-γ/TNF-α 刺激的中性粒细胞的激活状态，一氧化氮和 CD11b 表达增加以及粘附能力增加表明了这一点。在 G-CSF 刺激的中性粒细胞中，迁移状态增强，表现为 CXCR2 水平升高和迁移能力增加。这些数据表明，CerS6/C16-Cer 通过抑制 CD11b 和 CXCR2 的形成来介导反馈调节，CD11b 和 CXCR2 分别由 IFN-γ/TNF-α 或 G-CSF 诱导。我们得出结论，CerS6/C16-Cer 在 EAE 和 MS 的发展过程中可能通过抑制中性粒细胞的迁移和失活来介导抗炎作用。
Ceramides are mediators of inflammatory processes. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we observed that CerS6 mRNA expression was upregulated 15-fold in peripheral blood leukocytes before the onset of EAE symptoms. In peripheral blood leukocytes from MS patients, a 3.9-fold upregulation was found. Total genetic deletion of CerS6 and the selective deletion of CerS6 in peripheral blood leucocytes exacerbated the progression of clinical symptoms in EAE mice. This was associated with enhanced leukocyte, predominantly neutrophil infiltration and enhanced demyelination in the lumbar spinal cord of EAE mice. Interferon-gamma/tumor necrosis factor alpha (IFN-gamma/TNF-alpha) and granulocyte colony-stimulating factor (G-CSF) both drive EAE development and induce expression of the integrin CD11b and the chemokine receptor C-X-C motif chemokine receptor 2 (CXCR2), and we found they also induce CerS6 expression. In vivo, the genetic deletion of CerS6 enhanced the activation/migration of neutrophils, as reflected by an enhanced upregulation of CD11b and CXCR2. In vitro, the genetic deletion of CerS6 enhanced the activation status of IFN-gamma/TNF-alpha-stimulated neutrophils, as shown by increased expression of nitric oxide and CD11b and an increased adhesion capacity. In G-CSF-stimulated neutrophils, the migration status was enhanced, as reflected by an elevated level of CXCR2 and an increased migration capacity. These data suggest that CerS6/C16-Cer mediates feedback regulation by inhibiting the formation of CD11b and CXCR2, which are induced either by IFN-gamma/TNF-alpha or by G-CSF, respectively. We conclude that CerS6/C16-Cer mediates anti-inflammatory effects during the development of EAE and MS possibly by suppressing the migration and deactivation of neutrophils.