Indoxyl sulfate- and P-cresol-induced monocyte adhesion and migration is mediated by integrin-linked kinase-dependent podosome formation.
Indoxyl sulfate- and P-cresol-induced monocyte adhesion and migration is mediated by integrin-linked kinase-dependent podosome formation.
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DOI：
10.1038/s12276-022-00738-8
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发表时间：
2022-03
影响因子：
12.8
通讯作者：
Calleros L
中科院分区：
文献类型：
--
作者：
Campillo S;Bohorquez L;Gutiérrez-Calabrés E;García-Ayuso D;Miguel V;Griera M;Calle Y;de Frutos S;Rodríguez-Puyol M;Rodríguez-Puyol D;Calleros L
心血管疾病是慢性肾脏病（CKD）患者死亡的重要原因。蛋白结合的尿毒症毒素，如对甲苯基和硫酸吲哚酚（IS），在血液透析过程中清除不良，导致血管内皮功能障碍和白细胞外渗。这些过程可能与称为podosomes的动态粘附结构有关。几项研究表明整合素连接激酶（ILK）在整合素相关蛋白在podosomes中的积累中的作用。在这里，我们研究了参与ILK和podosome形成的粘附和外渗的单核细胞下对甲酚（PC）和IS曝光。用这些毒素孵育THP-1人单核细胞上调ILK激酶活性。总之，这两种毒素增加了细胞粘附，podosome形成，细胞外基质降解，和迁移的THP-1细胞，而ILK消耗特定的小干扰RNA抑制这些过程。有趣的是，在毒素刺激下，F-肌动蛋白与coronin共定位于podosome核心，而ILK共定位于podosome环。Podosome Wiskott-Aldrich综合征蛋白（WASP）相互作用蛋白（WASP）和AKT蛋白耗竭表明，单核细胞粘附依赖于podosome形成，ILK/AKT信号通路参与这些过程。离体实验表明，这两种毒素诱导粘附和podosome形成的白细胞从野生型小鼠，而这些影响没有观察到白细胞的条件ILK敲低动物。总之，在pc和IS刺激下，单核细胞通过ILK/AKT信号通路依赖性机制增加了足体形成和迁移能力，这可能导致血管损伤。因此，ILK可能是治疗CKD相关血管损伤的潜在治疗靶点。一种参与将结构蛋白组织成细胞膜突起的酶有助于促进慢性肾脏疾病中发生的白色血细胞的运动，并可能导致心血管损伤。来自西班牙马德里阿尔卡拉大学的Laura Calleros及其同事展示了肾脏衰竭时血液中积累的有毒代谢物如何诱导一种称为整合素相关激酶（ILK）的酶的活性。这种酶反过来又刺激白色血细胞形成称为足体的突起，使细胞更具移动的，使它们能够移出血管，进入周围组织，在那里它们可能引起炎症介导的损伤。ILK失活逆转了这些效应。因此，针对这种酶的治疗可能有助于限制慢性肾脏疾病的心血管并发症。
Cardiovascular disease is an important cause of death in patients with chronic kidney disease (CKD). Protein-bound uremic toxins, such as p-cresyl and indoxyl sulfate (IS), are poorly removed during hemodialysis, leading to vascular endothelial dysfunction and leukocyte extravasation. These processes can be related to dynamic adhesion structures called podosomes. Several studies have indicated the role of integrin-linked kinase (ILK) in the accumulation of integrin-associated proteins in podosomes. Here, we investigated the involvement of ILK and podosome formation in the adhesion and extravasation of monocytes under p-cresol (pc) and IS exposure. Incubation of THP-1 human monocyte cells with these toxins upregulated ILK kinase activity. Together, both toxins increased cell adhesion, podosome formation, extracellular matrix degradation, and migration of THP-1 cells, whereas ILK depletion with specific small interfering RNAs suppressed these processes. Interestingly, F-actin colocalized with cortactin in podosome cores, while ILK was colocalized in podosome rings under toxin stimulation. Podosome Wiskott-Aldrich syndrome protein (WASP)-interacting protein (WIP) and AKT protein depletion demonstrated that monocyte adhesion depends on podosome formation and that the ILK/AKT signaling pathway is involved in these processes. Ex vivo experiments showed that both toxins induced adhesion and podosome formation in leukocytes from wild-type mice, whereas these effects were not observed in leukocytes of conditional ILK-knockdown animals. In summary, under pc and IS stimulation, monocytes increase podosome formation and transmigratory capacity through an ILK/AKT signaling pathway-dependent mechanism, which could lead to vascular injury. Therefore, ILK could be a potential therapeutic target for the treatment of vascular damage associated with CKD. An enzyme involved in organizing structural proteins into protrusions of the cell membrane helps facilitate the movement of white blood cells that occurs in chronic kidney disease and can lead to cardiovascular damage. Laura Calleros from the University of Alcalá, Madrid, Spain, and colleagues showed how toxic metabolites that build up in the bloodstream as kidneys fail induce the activity of an enzyme called integrin-linked kinase (ILK). This enzyme in turn spurs white blood cells to form protrusions called podosomes that make the cells more mobile, enabling them to move out of blood vessels and into surrounding tissues where they can cause inflammation -mediated injury. ILK inactivation reversed these effects. Therapies that target the enzyme could therefore help limit the cardiovascular complications of chronic kidney disease.
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1016/j.biocel.2014.01.021
发表时间：
2014-05
影响因子：
4
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通讯作者：
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