Abstract
The macrophages from Crohn’s Disease (CD) patients are defective to control the replication of CD-associated adherent-invasive E. coli (AIEC). We aimed to identify the host factors associated with AIEC replication focusing on polymorphisms related to autophagy. Peripheral blood monocyte-derived macrophages (MDM), obtained from 95 CD patient, 30 ulcerative colitis (UC) patients and 15 healthy subjects, were genotyped for several CD-associated polymorphisms. AIEC bacteria survival increased within MDM from CD patients compared to UC (p = 0.0019). AIEC bacteria survival increased in patients with CD-associated polymorphism IRGM (p = 0.05) and reduced in those with CD-associated polymorphisms XBP-1 (p = 0.026) and ULK-1 (p = 0.033). AIEC infection led to an increase of pro-inflammatory cytokines IL-1β (p < 0.0001) and TNF-α (p < 0.0001) in CD macrophages. ULK-1 expression increased in AIEC-infected MDM from CD patients compared to MDM from UC patients or healthy subjects (p = 0.0056) and correlated with AIEC survival (p = 0.0013). Moreover, the expression of ULK-1 phosphorylation on Serine 757 decreased following to AIEC infection (p < 0.0001). Short-term silencing of ULK-1 and IRGM genes restricted and promote, respectively, AIEC survival within MDM (p = 0.0018 and p = 0.0291). In conclusion, the macrophage defect to mediate AIEC clearance in CD patients is linked to polymorphisms related to autophagy such as IRGM and ULK-1.
Highlights
Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) that can lead to altered quality of life and a high level of disability for the patients [1,2]
We confirmed that macrophages from Crohn’s Disease (CD) patients present a specific defect to control AIEC replication, and this is impacted by several CD-associated polymorphisms linked to autophagy
Conflicting results have been reported regarding the inflammatory response of E. coli-infected monocytes/macrophages from CD patients [14,15,34,35,36,37,38,39]
Summary
Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) that can lead to altered quality of life and a high level of disability for the patients [1,2]. In vitro studies have demonstrated that CD-associated AIEC are able to survive and replicate within macrophages, leading to increased secretion of tumor necrosis factor alpha (TNF-α) by infected macrophages [7,8,9,10,11,12,13,14]. We recently reported that AIEC bacteria were able to replicate within monocytes-derived macrophages (MDM) from CD patients but not within MDM from ulcerative colitis (UC) patients or healthy controls [14]. This observation suggests that CD MDM are deficient to control intracellular bacteria leading to specific inflammatory response [14]. Elliott and colleagues reported that MDM retrieved from CD patients were deficient to control several strains of E. coli including
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