Renal collecting duct epithelial cells react to pyelonephritis-associated Escherichia coli by activating distinct TLR4-dependent and -independent inflammatory pathways
Renal collecting duct epithelial cells react to pyelonephritis-associated Escherichia coli by activating distinct TLR4-dependent and -independent inflammatory pathways
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DOI：
10.4049/jimmunol.177.7.4773
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发表时间：
2006-10-01
影响因子：
4.4
通讯作者：
Vandewalle, Alain
中科院分区：
文献类型：
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作者：
Chassin, Cecilia;Goujon, Jean-Michel;Vandewalle, Alain
TLR4 在抵抗尿路病原性大肠杆菌 (UPEC) 引起的肾盂肾炎方面发挥着核心作用。有人提出，表达 TLR 的肾小管上皮细胞可能在炎症性疾病和启动宿主防御中发挥关键作用。在这项研究中，我们使用上行尿路感染的实验小鼠模型来表明 UPEC 分离株优先粘附在髓质集合管 (MCD) 嵌入细胞的顶端表面。携带 tlr4 失活突变的 UPEC 感染的 C3H/HeJ (Lps(d)) 小鼠无法清除肾脏细菌，并且与相比，促炎介质显着下降。感染野生型 C3H/HeOuJ (Lps(n)) 小鼠。然而，UPEC 感染的白细胞趋化剂 MIP-2 和 TNF-α 的表达水平仍然高于首次接触的 C3H/HeJ (Lps(d)) 小鼠。使用表达 TLR4 及其辅助分子 MD2、MyD88 和 CD14 的显微切割 Lps(n) MCD 的原代培养物，我们还表明 UPEC 刺激 TLR4 介导的、MyD88 依赖性的、包含 TIR 结构域的接头诱导 IFN-β 独立途径和 TLR4 独立途径，导致 MIP-2 的双极化分泌。 Lps(n) MCD 中 UPEC 对 TLR4 介导的途径的刺激导致 NF-kappa B、MAPK p38、ERK1/2 和 JNK 的激活。此外，UPEC 通过激活 TNF 受体相关因子 2-凋亡信号调节激酶 1-JNK 通路来刺激 TLR4 独立信号传导。这些发现表明，上皮集合管细胞通过几种不同的信号通路积极参与免疫反应的启动，并表明嵌入细胞在识别肾脏定植的 UPEC 中发挥着积极作用。
TLR4 plays a central role in resistance to pyelonephritis caused by uropathogenic Escherichia coli (UPEC). It has been suggested that renal tubule epithelial cells expressing TLRs may play a key role in inflammatory disorders and in initiating host defenses. In this study we used an experimental mouse model of ascending urinary tract infection to show that UPEC isolates preferentially adhered to the apical surface of medullary collecting duct (MCD) intercalated cells. UPEC-infected C3H/HeJ (Lps(d)) mice carrying an inactivating mutation of tlr4 failed to clear renal bacteria and exhibited a dramatic slump in proinflammatory mediators as compared with. infected wild-type C3H/HeOuJ (Lps(n)) mice. However, the level of expression of the leukocyte chemoattractants MIP-2 and TNF-alpha still remained greater in UPEC-infected than in naive C3H/HeJ (Lps(d)) mice. Using primary cultures of microdissected Lps(n) MCDs that expressed TLR4 and its accessory molecules MD2, MyD88, and CD14, we also show that UPECs stimulated both a TLR4-mediated, MyD88-dependent, TIR domain-containing adaptor-inducing IFN-beta-independent pathway and a TLR4-independent pathway, leading to bipolarized secretion of MIP-2. Stimulation by UPECs of the TLR4-mediated pathway in Lps(n) MCDs leads to the activation of NF-kappa B, and MAPK p38, ERK1/2, and JNK. In addition, UPECs stimulated TLR4-independent signaling by activating a TNF receptor-associated factor 2-apoptosis signal-regulatory kinase 1-JNK pathway. These findings demonstrate that epithelial collecting duct cells are actively involved in the initiation of an immune response via several distinct signaling pathways and suggest that intercalated cells play an active role in the recognition of UPECs colonizing the kidneys.