Defects in autophagy favour adherent-invasive Escherichia coli persistence within macrophages leading to increased pro-inflammatory response.
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-α 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.
Clermont Université, Université d'Auvergne, UMR-Inserm/Université d'Auvergne U1071, USC-INRA 2018, Clermont-Ferrand, France.
Pierre
P
Lapaquette
Marie-Agnès
MA
Bringer
Arlette
A
Darfeuille-Michaud
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D001422:Bacterial Adhesion; D058491:Bacterial Load; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D003424:Crohn Disease / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D004926:Escherichia coli / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D004927:Escherichia coli Infections / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D054884:Host-Pathogen Interactions; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011994:Recombinant Proteins / Q000096:biosynthesis; D000071456:Sequestosome-1 Protein
C518959:ATG16L1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D016207:Cytokines; D018836:Inflammation Mediators; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D011994:Recombinant Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D049452:Green Fluorescent Proteins; D019204:GTP-Binding Proteins; C513539:IRGM protein, human