Replication of Crohn's disease-associated AIEC within macrophages is dependent on TNF-α secretion
Replication of Crohn's disease-associated AIEC within macrophages is dependent on TNF-α secretion
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DOI：
10.1038/labinvest.2011.156
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发表时间：
2012-03-01
影响因子：
5
通讯作者：
Darfeuille-Michaud, Arlette
中科院分区：
文献类型：
--
作者：
Bringer, Marie-Agnes;Billard, Elisabeth;Darfeuille-Michaud, Arlette
与克罗恩病相关的粘附性和侵袭性大肠杆菌 (AIEC) 能够在巨噬细胞内活跃的吞噬溶酶体中存活并广泛复制。 AIEC 感染的巨噬细胞释放大量肿瘤坏死因子-α (TNF-α)，并且不会发生细胞死亡。本研究的目的是确定 AIEC 细菌可以通过诱导受感染的巨噬细胞释放大量 TNF-α 来获得什么益处，以及 TNF-α 的中和可以在多大程度上影响 AIEC 巨噬细胞内的复制。我们的结果表明，受感染巨噬细胞释放的 TNF-α 量与巨噬细胞内 AIEC 细菌的负载及其细胞内复制相关。 TNF-α的分泌与进入宿主细胞的细菌数量无关，因为当通过阻断脂筏依赖性和网格蛋白包被的凹坑依赖性内吞作用来减少巨噬细胞内化的细菌数量时，受感染的巨噬细胞分泌的TNF-α的量没有改变。有趣的是，当用外源性TNF-α刺激感染的巨噬细胞时，观察到细胞内AIEC LF82细菌数量呈剂量依赖性增加，并且使用抗TNF-α抗体中和AIEC感染的巨噬细胞分泌的TNF-α，导致巨噬细胞内细菌数量显着减少。这些结果表明AIEC细菌利用TNF-α作为特洛伊木马来确保其细胞内复制，因为AIEC细菌在巨噬细胞内的复制诱导TNF-α的释放，进而增加AIEC的巨噬细胞内复制。中和受感染巨噬细胞分泌的 TNF-α 可能是控制 AIEC 细胞内复制的有效策略。实验室调查 (2012) 92, 411-419; doi：10.1038/labinvest.2011.156； 2011 年 10 月 31 日在线发布
Adherent and invasive Escherichia coli (AIEC) associated with Crohn's disease are able to survive and to replicate extensively in active phagolysosomes within macrophages. AIEC-infected macrophages release large amounts of tumour necrosis factor-alpha (TNF-alpha) and do not undergo cell death. The aim of the present study was to determine what benefit AIEC bacteria could gain from inducing the release of large amounts of TNF-alpha by infected macrophages and to what extent the neutralization of TNF-alpha could affect AIEC intramacrophagic replication. Our results showed that the amount of TNF-alpha released by infected macrophages is correlated with the load of intramacrophagic AIEC bacteria and their intracellular replication. TNF-alpha secretion was not related to the number of bacteria entering host cells because when the number of bacteria internalized in macrophage was decreased by blocking lipid raft-dependent and clathrin-coated pits-dependent endocytosis, the amount of TNF-alpha secreted by infected macrophages was not modified. Interestingly, dose-dependent increases in the number of intracellular AIEC LF82 bacteria were observed when infected macrophages were stimulated with exogenous TNF-alpha, and neutralization of TNF-alpha secreted by AIEC-infected macrophages using anti-TNF-alpha antibodies induced a significant decrease in the number of intramacrophagic bacteria. These results indicate that AIEC bacteria use TNF-alpha as a Trojan horse to ensure their intracellular replication because replication of AIEC bacteria within macrophages induces the release of TNF-alpha, which in turn increases the intramacrophagic replication of AIEC. Neutralizing TNF-alpha secreted by infected macrophages may represent an effective strategy to control AIEC intracellular replication. Laboratory Investigation (2012) 92, 411-419; doi:10.1038/labinvest.2011.156; published online 31 October 2011