Caveolin-1 Deficiency Dampens Toll-Like Receptor 4 Signaling through eNOS Activation
Caveolin-1 Deficiency Dampens Toll-Like Receptor 4 Signaling through eNOS Activation
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DOI：
10.2353/ajpath.2010.091088
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发表时间：
2010-05-01
影响因子：
6
通讯作者：
Zhao, You-Yang
中科院分区：
文献类型：
--
作者：
Mirza, Muhammad K.;Yuan, Jun;Zhao, You-Yang
Caveolin-1（Cav 1）是Caveolae的支架蛋白，在宿主防御和炎症反应中起重要作用。然而，这些行动的潜在分子基础仍然难以捉摸。在这里，使用Cav 1和NOS 3基因缺失的双突变小鼠，我们表明，慢性内皮型一氧化氮合酶（eNOS）激活继发于Cav 1的损失，通过酪氨酸硝化介导的白细胞介素-1受体相关激酶（IRAK）4，所需的核因子-κ B激活和先天免疫的信号传导组件的损害提供了一个至关重要的免疫调节功能。我们观察到eNOS依赖性的血浆促炎细胞因子浓度的降低和Cav 1（-/-）小鼠在脂多糖攻击后的存活率的显着改善。eNOS的激活继发于Cav 1的缺失，导致核因子-κ B的激活在对脂多糖攻击的反应中降低，从而保护动物免受脂多糖诱导的肺损伤。IRAK 4显着硝化Cav 1缺陷的内皮细胞，而eNOS缺失Cav 1缺陷的内皮细胞导致IRAK 4硝化显着减少，并恢复脂多糖攻击后的炎症反应。此外，体外硝化IRAK 4导致激酶活性受损。因此，继发于Cavl损失的eNOS活化通过IRAK 4硝化和由此产生的激酶活性损伤发出抑制对脂多糖的先天免疫应答的信号，并因此减轻炎性肺损伤。(Am J Pathol 2010，176：2344-2351; DOI：10.2353/ajpath.2010.091088）
Caveolin-1 (Cav1), the scaffolding protein of caveolae, has been shown to play an important role in host defense and inflammation. However, the underlying molecular basis for these actions remains elusive. Here, using double mutant mice with genetic deletions of Cav1 and NOS3, we show that chronic endothelial nitric oxide synthase (eNOS) activation secondary to loss of Cav1 serves a crucial immunomodulatory function through tyrosine nitration-mediated impairment of interleukin-1 receptor associated kinase (IRAK)4, a signaling component required for nuclear factor-kappa B activation and innate immunity. We observed an eNOS-dependent decrease in the plasma concentration of pro-inflammatory cytokines and marked improvement of survival in Cav1(-/-) mice following lipopolysaccharide challenge. Activation of eNOS secondary to loss of Cav1 resulted in decreased activation of nuclear factor-kappa B in response to lipopolysaccharide challenge, and thereby protected the animals from lipopolysaccharide-induced lung injury. IRAK4 was prominently nitrated in Cav1-deficient endothelial cells, whereas eNOS deletion in Cav1-deficient endothelial cells resulted in marked decrease of IRAK4 nitration and restored the inflammatory response after lipopolysaccharide challenge. Furthermore, in vitro nitration of IRAK4 resulted in impairment of the kinase activity. Thus, eNOS activation secondary to loss of Cav1 signals dampening of the innate immune response to lipopolysaccharide through IRAK4 nitration and the resultant impairment of kinase activity, and consequently mitigates inflammatory lung injury. (Am J Pathol 2010, 176:2344-2351; DOI: 10.2353/ajpath.2010.091088)