Sickle cell disease activates peripheral blood mononuclear cells to induce cathepsins k and v activity in endothelial cells.
Sickle cell disease activates peripheral blood mononuclear cells to induce cathepsins k and v activity in endothelial cells.
复制标题
作者：
Keegan PM;Surapaneni S;Platt MO
镰状细胞病是一种遗传性疾病，会增加全身炎症和儿童中风的风险，但镰状细胞引起的炎症和动脉重塑之间的联系尚不清楚。组织蛋白是血管内皮细胞和单核细胞来源的巨噬细胞在动脉粥样硬化中分泌的强大的弹性蛋白酶和胶原酶，但它们在镰状细胞疾病中的作用尚未被研究。在这里，我们研究了肿瘤坏死因子α和循环中单个核细胞与人主动脉内皮细胞(ECs)的黏附如何增加活性组织蛋白K和V作为动脉壁炎症的模型。用肿瘤坏死因子α刺激内皮细胞，并与镰状(SS)或正常(AA)血红蛋白纯合者的外周血单个核细胞(PBMC)共同培养。肿瘤坏死因子α是诱导组织蛋白酶K活性所必需的，但与单个核细胞结合或肿瘤坏死因子α均可增加组织蛋白酶V活性。SS PBMC是独一无二的，它们在没有外源性肿瘤坏死因子α的情况下诱导内皮细胞中的组织蛋白酶K(n=4，P<；0.05)。抑制c-Jun氨基末端激酶(JNK)可使组织蛋白K和V的活性分别降低60%和51%。炎症和激活的循环单个核细胞共同通过JNK信号上调组织蛋白酶活性，确定新的药物靶点来阻断镰状细胞疾病儿童动脉中观察到的加速病理。
Sickle cell disease is a genetic disease that increases systemic inflammation as well as the risk of pediatric strokes, but links between sickle-induced inflammation and arterial remodeling are not clear. Cathepsins are powerful elastases and collagenases secreted by endothelial cells and monocyte-derived macrophages in atherosclerosis, but their involvement in sickle cell disease has not been studied. Here, we investigated how tumor necrosis alpha (TNFα) and circulating mononuclear cell adhesion to human aortic endothelial cells (ECs) increase active cathepsins K and V as a model of inflammation occurring in the arterial wall. ECs were stimulated with TNFα and cultured with peripheral blood mononuclear cells (PBMCs) from persons homozygous for sickle (SS) or normal (AA) hemoglobin. TNFα was necessary to induce cathepsin K activity, but either PBMC binding or TNFα increased cathepsin V activity. SS PBMCs were unique; they induced cathepsin K in ECs without exogenous TNFα (n = 4, P < 0.05). Inhibition of c-Jun N-terminal kinase (JNK) significantly reduced cathepsins K and V activation by 60% and 51%, respectively. Together, the inflammation and activated circulating mononuclear cells upregulate cathepsin activity through JNK signaling, identifying new pharmaceutical targets to block the accelerated pathology observed in arteries of children with sickle cell disease.