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首页> 外文期刊>Thrombosis and Haemostasis: Journal of the International Society on Thrombosis and Haemostasis >Cofactor-independent antiphospholipid antibodies activate the NLRP3-inflammasome via endosomal NADPH-oxidase: implications for the antiphospholipid syndrome
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Cofactor-independent antiphospholipid antibodies activate the NLRP3-inflammasome via endosomal NADPH-oxidase: implications for the antiphospholipid syndrome

机译：不依赖辅因子的抗磷脂抗体通过内体NADPH氧化酶激活NLRP3-炎症小体：对抗磷脂综合征的影响

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The antiphospholipid syndrome (APS) is an autoimmune disease char, acterised by thromboembolic events and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). Here we show that three cofactor independent human monoclonal aPL can induce transcription of NLRP3 and caspase-1 resulting in inflammasome activation specific for NLRP3. This depends fully on activation of endosomal NADPH-oxidase-2 (NOX2) by aPL. Activation of NOX2 and subsequent inflammasome activation by aPL are independent from TLR2 or TLR4. While endosomal superoxide production induces caspase-1 and NLRP3 transcription, it does not affect prae-IL-1 beta transcription. Therefore, release of IL-1 beta occurs only after activation of additional pathways like TLR7/8 or TLR2. All effects exerted by the monoclonal aPL can be reproduced with IgG fractions of APS patients proving that the monoclonal aPL are representative for the APS. IgG fractions of healthy controls or patients suffering from systemic lupus erythematosus have no effect. In a mouse model of the APS we can show inflammasome activation in vivo. Furthermore, mononuclear cells isolated from patients with the APS show an increased expression of caspase-1 and NLRP3 which is accompanied by a three-fold increased serum concentration of IL-1 beta suggesting chronic inflammasome activation in APS patients. In summary, we provide further evidence that endosomal NOX2 can be activated by cofactor independent aPL. This leads to induction of the NLRP3 inflammasome. Our data indicate that cofactor independent aPL might contribute significantly to the pathogenesis of the APS.
机译：抗磷脂综合征（APS）是一种自身免疫性疾病，在抗磷脂抗体（aPL）存在的情况下，由血栓栓塞事件和/或妊娠发病引起。在这里，我们显示了三个不依赖辅因子的人单克隆aPL可以诱导NLRP3和caspase-1的转录，从而导致特异性针对NLRP3的炎症小体活化。这完全取决于aPL对内体NADPH-氧化酶2（NOX2）的激活。 NOX2的激活以及随后aPL激活的炎性体独立于TLR2或TLR4。内体超氧化物的产生诱导caspase-1和NLRP3转录，但它不影响prae-IL-1 beta转录。因此，仅在激活其他途径（如TLR7 / 8或TLR2）后才释放IL-1β。单克隆aPL发挥的所有作用都可以用APS患者的IgG部分重现，证明单克隆aPL代表了APS。健康对照或患有系统性红斑狼疮的患者的IgG分数无效。在APS的小鼠模型中，我们可以显示体内的炎性体激活。此外，从患有APS的患者中分离出的单核细胞显示caspase-1和NLRP3的表达增加，同时血清IL-1β的浓度增加了三倍，表明APS患者的慢性炎症小体活化。总之，我们提供了进一步的证据，证明内体NOX2可以被辅因子非依赖性aPL激活。这导致了NLRP3炎性体的诱导。我们的数据表明独立于辅因子的aPL可能对APS的发病机理有重要贡献。

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