Du Feifei, Wang Yongzhi, Ding Zhiyi, Laschke Matthias W, Thorlacius Henrik
Department of Clinical Sciences, Section of Surgery, Lund University, Malmö, Sweden.
Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany.
Eur Surg Res. 2019;60(1-2):53-62. doi: 10.1159/000497435. Epub 2019 Mar 25.
Polyphosphates (PolyPs) have been reported to exert pro-inflammatory effects. However, the molecular mechanisms regulating PolyP-provoked tissue accumulation of leukocytes are not known. The aim of the present investigation was to determine the role of specific adhesion molecules in PolyP-mediated leukocyte recruitment.
PolyPs and TNF-α were intrascrotally administered, and anti-P-selectin, anti-E-selectin, anti-P-selectin glycoprotein ligand-1 (PSGL-1), anti-membrane-activated complex-1 (Mac-1), anti-lymphocyte function antigen-1 (LFA-1), and neutrophil depletion antibodies were injected intravenously or intraperitoneally. Intravital microscopy of the mouse cremaster microcirculation was used to examine leukocyte-endothelium interactions and recruitment in vivo.
Intrascrotal injection of PolyPs increased leukocyte accumulation. Depletion of neutrophils abolished PolyP-induced leukocyte-endothelium interactions, indicating that neutrophils were the main leukocyte subtype responding to PolyP challenge. Immunoneutralization of P-selectin and PSGL-1 abolished PolyP-provoked neutrophil rolling, adhesion, and emigration. Moreover, immunoneutralization of Mac-1 and LFA-1 had no impact on neutrophil rolling but markedly reduced neutrophil adhesion and emigration evoked by PolyPs.
These results suggest that P-selectin and PSGL-1 exert important roles in PolyP-induced inflammatory cell recruitment by mediating neutrophil rolling. In addition, our data show that Mac-1 and LFA-1 are necessary for supporting PolyP-triggered firm adhesion of neutrophils to microvascular endothelium. These novel findings define specific molecules as potential targets for pharmacological intervention in PolyP-dependent inflammatory diseases.
据报道，多聚磷酸盐（PolyPs）具有促炎作用。然而，调节PolyP引发的白细胞组织积聚的分子机制尚不清楚。本研究的目的是确定特定黏附分子在PolyP介导的白细胞募集中的作用。
将PolyPs和肿瘤坏死因子-α（TNF-α）经阴囊内给药，并静脉内或腹腔内注射抗P-选择素、抗E-选择素、抗P-选择素糖蛋白配体-1（PSGL-1）、抗膜攻击复合物-1（Mac-1）、抗淋巴细胞功能相关抗原-1（LFA-1）以及中性粒细胞耗竭抗体。采用小鼠提睾肌微循环活体显微镜检查来检测体内白细胞与内皮细胞的相互作用和募集情况。
经阴囊内注射PolyPs可增加白细胞积聚。中性粒细胞耗竭可消除PolyP诱导的白细胞与内皮细胞的相互作用，表明中性粒细胞是对PolyP刺激作出反应的主要白细胞亚型。P-选择素和PSGL-1的免疫中和消除了PolyP引发的中性粒细胞滚动、黏附和移出。此外，Mac-1和LFA-1的免疫中和对中性粒细胞滚动没有影响，但显著降低了PolyPs引起的中性粒细胞黏附和移出。
这些结果表明，P-选择素和PSGL-1通过介导中性粒细胞滚动在PolyP诱导的炎症细胞募集中发挥重要作用。此外，我们的数据表明，Mac-1和LFA-1对于支持PolyP触发的中性粒细胞与微血管内皮细胞的牢固黏附是必需的。这些新发现确定了特定分子作为PolyP依赖性炎症疾病药理干预的潜在靶点。
