Godaly G, Bergsten G, Hang L, Fischer H, Frendéus B, Lundstedt A C, Samuelsson M, Samuelsson P, Svanborg C
Department of Laboratory Medicine, Division of Microbiology, Immunology and Glycobiology (MIG), Lund University, Lund, Sweden, and The Wright Flemming Institute, Imperial College School of Medicine, London, England.
J Leukoc Biol. 2001 Jun;69(6):899-906.
Neutrophil migration to infected mucosal sites involves a series of complex interactions with molecules in the lamina propria and at the epithelial barrier. Much attention has focussed on the vascular compartment and endothelial cells, but less is known about the molecular determinants of neutrophil behavior in the periphery. We have studied urinary tract infections (UTIs) to determine the events that initiate neutrophil recruitment and interactions of the recruited neutrophils with the mucosal barrier. Bacteria activate a chemokine response in uroepithelial cells, and the chemokine repertoire depends on the bacterial virulence factors and on the specific signaling pathways that they activate. In addition, epithelial chemokine receptor expression is enhanced. Interleukin (IL)-8 and CXCR1 direct neutrophil migration across the epithelial barrier into the lumen. Indeed, mIL-8Rh knockout mice showed impaired transepithelial neutrophil migration, with tissue accumulation of neutrophils, and these mice developed renal scarring. They had a defective antibacterial defense and developed acute pyelonephritis with bacteremia. Low CXCR1 expression was also detected in children with acute pyelonephritis. These results demonstrate that chemokines and chemokine receptors are essential to orchestrate a functional antimicrobial defense of the urinary tract mucosa. Mutational inactivation of the IL-8R caused both acute disease and chronic tissue damage.
中性粒细胞向感染的黏膜部位迁移涉及与固有层和上皮屏障中的分子发生一系列复杂的相互作用。人们大多关注血管腔室和内皮细胞，但对于中性粒细胞在外周行为的分子决定因素了解较少。我们研究了尿路感染（UTIs），以确定启动中性粒细胞募集的事件以及募集到的中性粒细胞与黏膜屏障的相互作用。细菌激活尿路上皮细胞中的趋化因子反应，趋化因子库取决于细菌毒力因子及其激活的特定信号通路。此外，上皮趋化因子受体表达增强。白细胞介素（IL）-8和CXCR1引导中性粒细胞穿过上皮屏障进入管腔。实际上，mIL-8Rh基因敲除小鼠的跨上皮中性粒细胞迁移受损，中性粒细胞在组织中积聚，并且这些小鼠出现了肾瘢痕形成。它们的抗菌防御存在缺陷，并发展为伴有菌血症的急性肾盂肾炎。在急性肾盂肾炎患儿中也检测到CXCR1表达较低。这些结果表明趋化因子和趋化因子受体对于协调尿路黏膜的功能性抗菌防御至关重要。IL-8R的突变失活导致了急性疾病和慢性组织损伤。
