Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
Crit Care Med. 2012 Sep;40(9):2631-7. doi: 10.1097/CCM.0b013e318258fb70.
To investigate the role of toll-like receptor 9 on sepsis-induced failure of neutrophil recruitment to the site of infection.
Prospective experimental study.
University research laboratory.
Model of polymicrobial sepsis induced by cecal ligation and puncture in wild-type and toll-like receptor 9-deficient mice.
Toll-like receptor 9-deficient mice with cecal ligation and puncture-induced severe sepsis did not demonstrate failure of neutrophil migration and consequently had a low systemic inflammatory response and a high survival rate. Upon investigating the mechanism by which toll-like receptor 9 deficiency prevents the failure of neutrophil migration, it was found that neutrophils derived from toll-like receptor 9--deficient mice with cecal ligation and puncture-induced severe sepsis expressed high levels of chemokine C-X-C motif receptor 2 (CXCR2) and had reduced induction of G-protein-coupled receptor kinase 2.
These findings suggest that the poor outcome of severe sepsis is associated with toll-like receptor 9 activation in neutrophils, which triggers G-protein-coupled receptor kinase 2 expression and CXCR2 downregulation. These events account for the reduction of neutrophil migration to the site of infection, with consequent spreading of the infection, onset of the systemic inflammatory response, and a decrease in survival.
探讨 Toll 样受体 9 在脓毒症导致中性粒细胞向感染部位募集失败中的作用。
前瞻性实验研究。
大学研究实验室。
通过盲肠结扎和穿刺在野生型和 Toll 样受体 9 缺陷型小鼠中建立多微生物脓毒症模型。
盲肠结扎和穿刺诱导严重脓毒症的 Toll 样受体 9 缺陷型小鼠未表现出中性粒细胞迁移失败，因此全身炎症反应较低，存活率较高。在研究 Toll 样受体 9 缺陷如何防止中性粒细胞迁移失败的机制时，发现盲肠结扎和穿刺诱导严重脓毒症的 Toll 样受体 9 缺陷型小鼠来源的中性粒细胞表达高水平的趋化因子 C-X-C 基序受体 2（CXCR2），并且 G 蛋白偶联受体激酶 2 的诱导减少。
这些发现表明，严重脓毒症不良预后与中性粒细胞中 Toll 样受体 9 的激活有关，后者触发 G 蛋白偶联受体激酶 2 的表达和 CXCR2 的下调。这些事件导致中性粒细胞向感染部位的迁移减少，随后感染扩散、全身炎症反应的发生以及存活率降低。
