Factor VIIa induces anti-inflammatory signaling via EPCR and PAR1
Factor VIIa induces anti-inflammatory signaling via EPCR and PAR1
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DOI：
10.1182/blood-2017-10-813527
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发表时间：
2018-05-24
期刊：
影响因子：
20.3
通讯作者：
Pendurthi, Usha R.
中科院分区：
文献类型：
--
作者：
Kondreddy, Vijay;Wang, Jue;Pendurthi, Usha R.
最近的研究表明，内皮细胞蛋白C受体（EPCR）除了与已知的配体蛋白C和活化蛋白C（APC）相互作用外，还与多种配体相互作用。我们在早期的研究中发现，促凝血凝血因子VIIa（FVIIa）结合EPCR，下调EPCR介导的抗凝作用，并诱导内皮屏障保护作用。在这里，我们研究了FVIIa与EPCR的相互作用对内皮细胞炎症和脂多糖（LPS）诱导的体内炎症反应的影响。用FVIIa处理内皮细胞抑制肿瘤坏死因子α（TNF-α）和LPS诱导的细胞粘附分子表达和单核细胞与内皮细胞的粘附。通过特异性抗体或小干扰RNA抑制EPCR或蛋白酶激活受体1（PAR1），可消除FVIIa诱导的对TNF-α和LPS诱导的细胞粘附分子和白细胞介素-6表达的抑制。β-Arrestin-1沉默阻断了内皮细胞中FVIIa诱导的抗炎作用。体内研究表明，FVIIa治疗显著抑制LPS诱导的炎性细胞因子和天然免疫细胞向野生型和EPCR过表达小鼠肺中的浸润，但在EPCR缺陷小鼠中没有。机制研究显示，FVIIa处理抑制TNF-α诱导的ERK 1/2、p38 MAPK、JNK、NF-κ B和C-Jun活化，表明FVIIa介导的信号传导阻断TNF-α诱导的信号传导级联中的上游信号传导事件。FVIIa治疗损害了TNF受体相关因子2向TNF受体1信号传导复合物的募集。总体而言，我们目前的数据提供了令人信服的证据，即FVIIa与EPCR的结合通过PAR 1和β-抑制蛋白-1依赖性途径激发抗炎信号传导。目前的研究表明，FVIIa的新的治疗潜力，这是目前在临床上用于治疗出血性疾病。
Recent studies show that endothelial cell protein C receptor (EPCR) interacts with diverse ligands, in addition to its known ligands protein C and activated protein C (APC). We showed in earlier studies that procoagulant clotting factor VIIa (FVIIa) binds EPCR and downregulates EPCR-mediated anticoagulation and induces an endothelial barrier protective effect. Here, we investigated the effect of FVIIa's interaction with EPCR on endothelial cell inflammation and lipopolysaccharide (LPS)-induced inflammatory responses in vivo. Treatment of endothelial cells with FVIIa suppressed tumor necrosis factor alpha (TNF-alpha)and LPS-induced expression of cellular adhesion molecules and adherence of monocytes to endothelial cells. Inhibition of EPCR or protease-activated receptor 1 (PAR1) by either specific antibodies or small interfering RNA abolished the FVIIa-induced suppression of TNF-alpha- and LPS-induced expression of cellular adhesion molecules and interleukin-6. beta-Arrestin-1 silencing blocked the FVIIa-induced anti-inflammatory effect in endothelial cells. In vivo studies showed that FVIIa treatment markedly suppressed LPS-induced inflammatory cytokines and infiltration of innate immune cells into the lung in wild-type and EPCR-overexpressing mice, but not in EPCR-deficient mice. Mechanistic studies revealed that FVIIa treatment inhibited TNF-alpha-induced ERK1/2, p38 MAPK, JNK, NF-kappa B, and C-Jun activation indicating that FVIIa-mediated signaling blocks an upstream signaling event in TNF alpha-induced signaling cascade. FVIIa treatment impaired the recruitment of TNF-receptor-associated factor 2 into the TNF receptor 1 signaling complex. Overall, our present data provide convincing evidence that FVIIa binding to EPCR elicits anti-inflammatory signaling via a PAR1- and beta-arrestin-1 dependent pathway. The present study suggests new therapeutic potentials for FVIIa, which is currently in clinical use for treating bleeding disorders.