Epithelial C5aR1 Signaling Enhances Uropathogenic Escherichia coli Adhesion to Human Renal Tubular Epithelial Cells.
Epithelial C5aR1 Signaling Enhances Uropathogenic Escherichia coli Adhesion to Human Renal Tubular Epithelial Cells.
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上皮 C5aR1 信号传导增强尿路致病性大肠杆菌对人肾小管上皮细胞的粘附
DOI：
10.3389/fimmu.2018.00949
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发表时间：
2018
影响因子：
7.3
通讯作者：
Li K
中科院分区：
文献类型：
--
作者：
Song Y;Wu KY;Wu W;Duan ZY;Gao YF;Zhang LD;Chong T;Garstka MA;Zhou W;Li K
在小鼠上行性尿路感染模型中的近期研究表明，C5a/C5aR1相互作用通过增强细菌对肾小管上皮细胞（RTECs）的黏附/定植，在肾脏感染的发展中起致病作用。在本研究中，我们将这些观察结果扩展到人类。我们发现肾小管上皮细胞的C5aR1信号传导参与促进尿路致病性大肠杆菌（UPEC）对宿主细胞的黏附/侵袭。用C5a刺激原代培养的RTEC，导致UPEC对RTEC的黏附/侵袭显著增加。这与C5a刺激后RTEC中末端α -甘露糖基残基（Man）（大肠杆菌1型菌毛的一种配体）表达增强有关。机制研究表明，C5aR1介导的ERK1/2/NF - κB激活以及促炎细胞因子产生（即TNF - α）的上调至少部分是Man表达上调和细菌黏附的原因。临床样本研究显示，在正常人肾活检的肾小管上皮中可明显检测到C5aR1和Man，并且UPEC以依赖d -甘露糖的方式与上皮结合。此外，与健康对照组相比，尿路感染患者尿液中的C5a水平显著升高。因此，我们的数据表明，与在小鼠中的观察结果一致，人肾小管上皮细胞的C5aR1信号传导可上调RTEC中的Man表达，从而增强UPEC对RTEC的黏附和侵袭。这也表明C5a/C5aR1相互作用上调肾小管上皮中Man表达在体内的相关性及其对肾脏感染的潜在影响。
Recent work in a murine model of ascending urinary tract infection has suggested that C5a/C5aR1 interactions play a pathogenic role in the development of renal infection through enhancement of bacterial adhesion/colonization to renal tubular epithelial cells (RTECs). In the present study, we extended these observations to human. We show that renal tubular epithelial C5aR1 signaling is involved in promoting uropathogenic Escherichia coli (UPEC) adhesion/invasion of host cells. Stimulation of primary cultures of RTEC with C5a resulted in significant increases in UPEC adhesion/invasion of the RTEC. This was associated with enhanced expression of terminal α-mannosyl residues (Man) (a ligand for type 1 fimbriae of E. coli) in the RTEC following C5a stimulation. Mechanism studies revealed that C5aR1-mediated activation of ERK1/2/NF-κB and upregulation of proinflammatory cytokine production (i.e., TNF-α) is at least partly responsible for the upregulation of Man expression and bacterial adhesion. Clinical sample studies showed that C5aR1 and Man were clearly detected in the renal tubular epithelium of normal human kidney biopsies, and UPEC bound to the epithelium in a d-mannose-dependent manner. Additionally, C5a levels were significantly increased in urine of urinary tract infection patients compared with healthy controls. Our data therefore demonstrate that, in agreement with observations in mice, human renal tubular epithelial C5aR1 signaling can upregulate Man expression in RTEC, which enhances UPEC adhesion to and invasion of RTEC. It also suggests the in vivo relevance of upregulation of Man expression in renal tubular epithelium by C5a/C5aR1 interactions and its potential impact on renal infection.