Nitric Oxide Is Involved in Mycobacterium bovis Bacillus Calmette-Guerin-Activated Jagged1 and Notch1 Signaling
Nitric Oxide Is Involved in Mycobacterium bovis Bacillus Calmette-Guerin-Activated Jagged1 and Notch1 Signaling
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DOI：
10.4049/jimmunol.0903174
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发表时间：
2010-03-15
影响因子：
4.4
通讯作者：
Balaji, Kithiganahalli N.
中科院分区：
文献类型：
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作者：
Kapoor, Nisha;Narayana, Yeddula;Balaji, Kithiganahalli N.
致病性分枝杆菌已经进化出独特的策略来在巨噬细胞的恶劣环境中生存。由宿主在感染期间产生的NO对关键信号级联的调节在整体细胞命运决定中具有至关重要的作用。我们表明，NO是一个关键因素，在牛分枝杆菌卡介苗介导的Notch 1激活，作为激活的Notch 1或表达的Notch 1靶基因基质金属蛋白酶-9（MMP-9）或Hes 1被废除的巨噬细胞诱导型NO合酶（iNOS）敲除（iNOS（-/-）），但不是从野生型，小鼠。有趣的是，Notch 1配体Jagged 1的表达在M.牛杆菌卡介苗刺激的iNOS（-/-）巨噬细胞以及Jagged 1表达或Notch信号传导的丧失可以通过NO供体来挽救。信号扰动或遗传方法暗示MMP-9或Hes 1的稳健表达需要TLR 2和经典Notch 1-PI 3 K级联之间的协同作用和串扰。此外，CSL/RBP-Jk有助于TLR 2介导的MMP-9或Hes 1的表达。相关证据表明，在CNS结核的小鼠模型中，该机制仅在来自WT而不是来自iNOS（-/-）小鼠的脑中体内起作用。重要的是，我们证明了Notch 1信号在结核分枝杆菌感染的结核性脑膜炎患者脑内肉芽肿病变中的体内激活。目前的研究确定NO作为一种病理联系，调节TLR 2与Notch 1-PI 3 K信号或Jagged 1的直接合作，以调节TLR 2反应的特定组分。这些发现提供了新的见解Notch 1，TLR 2和NO信号整合在一个串扰，调节巨噬细胞中的一组定义的效应器功能的机制。免疫学杂志，2010，184：3117-3126。
Pathogenic mycobacteria have evolved unique strategies to survive within the hostile environment of macrophages. Modulation of key signaling cascades by NO, generated by the host during infection, assumes critical importance in overall cell-fate decisions. We show that NO is a critical factor in Mycobacterium bovis bacillus Calmette-Guerin-mediated Notch1 activation, as the generation of activated Notch1 or expression of Notch1 target genes matrix metalloproteinase-9 (MMP-9) or Hes1 was abrogated in macrophages derived from inducible NO synthase (iNOS) knockout (iNOS(-/-)), but not from wild-type, mice. Interestingly, expression of the Notch1 ligand Jagged1 was compromised in M. bovis bacillus Calmette-Guerin-stimulated iNOS(-/-) macrophages, and loss of Jagged1 expression or Notch signaling could be rescued by NO donors. Signaling perturbations or genetic approaches implicated that robust expression of MMP-9 or Hes1 required synergy and cross talk between TLR2 and canonical Notch1-PI3K cascade. Further, CSL/RBP-Jk contributed to TLR2-mediated expression of MMP-9 or Hes1. Correlative evidence shows that, in a murine model for CNS tuberculosis, this mechanism operates in vivo only in brains derived from WT but not from iNOS(-/-) mice. Importantly, we demonstrate the activation of Notch1 signaling in vivo in granulomatous lesions in the brains of Mycobacterium tuberculosis-infected human patients with tuberculous meningitis. Current investigation identifies NO as a pathological link that modulates direct cooperation of TLR2 with Notch1-PI3K signaling or Jagged1 to regulate specific components of TLR2 responses. These findings provide new insights into mechanisms by which Notch1, TLR2, and NO signals are integrated in a cross talk that modulates a defined set of effector functions in macrophages. The Journal of Immunology, 2010, 184: 3117-3126.