Defects in autophagy favour adherent-invasive Escherichia coli persistence within macrophages leading to increased pro-inflammatory response
Defects in autophagy favour adherent-invasive Escherichia coli persistence within macrophages leading to increased pro-inflammatory response
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DOI：
10.1111/j.1462-5822.2012.01768.x
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发表时间：
2012-06-01
影响因子：
3.4
通讯作者：
Darfeuille-Michaud, Arlette
中科院分区：
文献类型：
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作者：
Lapaquette, Pierre;Bringer, Marie-Agnes;Darfeuille-Michaud, Arlette
在克罗恩病（CD）患者的回肠病变异常定植致病性粘附-侵袭性大肠杆菌（AIEC）。AIEC细菌能够在内吞液泡裂解后在上皮细胞内和大液泡内的巨噬细胞内复制。NOD2、ATG16L1和IRGM中cd相关的多态性影响细菌自噬，这是一种重要的先天免疫机制。我们先前确定自噬缺陷会损害上皮细胞控制AIEC复制的能力。AIEC在上皮细胞和巨噬细胞中的表现不同，因此我们研究了自噬缺陷对AIEC巨噬细胞内复制和促炎细胞因子反应的影响。AIEC细菌在吞噬部位诱导自噬机制的募集，功能性自噬限制了AIEC巨噬细胞内的复制。ATG16L1、IRGM或NOD2表达受损导致AIEC感染后巨噬细胞内AIEC增加，IL-6和TNF-a分泌增加。相反，即使在nod2缺乏的情况下，强迫诱导自噬也会减少巨噬细胞内AIEC的数量和促炎细胞因子的释放。根据我们的研究结果，我们推测刺激CD患者的自噬将是一种有效的治疗策略，可以同时抑制细胞内AIEC的复制并减缓炎症反应。
Ileal lesions in Crohn's disease (CD) patients are abnormally colonized by pathogenic adherent-invasive Escherichia coli (AIEC). AIEC bacteria are able to replicate within epithelial cells after lysis of the endocytic vacuole and within macrophages in a large vacuole. CD-associated polymorphisms in NOD2, ATG16L1 and IRGM affect bacterial autophagy, a crucial innate immunity mechanism. We previously determined that defects in autophagy impaired the ability of epithelial cells to control AIEC replication. AIEC behave differently within epithelial cells and macrophages and so we investigated the impact of defects in autophagy on AIEC intramacrophagic replication and pro-inflammatory cytokine response. AIEC bacteria induced the recruitment of the autophagy machinery at the site of phagocytosis, and functional autophagy limited AIEC intramacrophagic replication. Impaired ATG16L1, IRGM or NOD2 expression induced increased intramacrophagic AIEC and increased secretion of IL-6 and TNF-a in response to AIEC infection. In contrast, forced induction of autophagy decreased the numbers of intramacrophagic AIEC and pro-inflammatory cytokine release, even in a NOD2-deficient context. On the basis of our findings, we speculate that stimulating autophagy in CD patients would be a powerful therapeutic strategy to concomitantly restrain intracellular AIEC replication and slow down the inflammatory response.