Interleukin-1 Receptor Signaling Protects Mice from Lethal Intestinal Damage Caused by the Attaching and Effacing Pathogen Citrobacter rodentium

Abstract

Enteropathogenic Escherichia coli, enterohemorrhagic E. coli, and Citrobacter rodentium are classified as attaching and effacing pathogens based on their ability to adhere to the intestinal epithelium via actin-filled membranous protrusions (pedestals). Infection of mice with C. rodentium causes a breach of the intestinal epithelial barrier, leading to colitis via a vigorous inflammatory response resulting in diarrhea and a protective antibody response that clears the pathogen. Here we show that interleukin-1 receptor (IL-1R) signaling protects mice following infection with C. rodentium. Upon infection, mice lacking the type I IL-1R exhibit increased mortality together with severe colitis characterized by intramural colonic bleeding and intestinal damage including gangrenous mucosal necrosis, phenotypes also evident in MyD88-deficient mice. However, unlike MyD88 ؊/؊ mice, IL-1R ؊/؊ mice do not exhibit increased pathogen loads in the colon, delays in the recruitment of innate immune cells such as neutrophils, or defects in the capacity to replace damaged enterocytes. Further, we demonstrate that IL-1R ؊/؊ mice have an increased predisposition to intestinal damage caused by C. rodentium but not to that caused by chemical irritants, such as dextran sodium sulfate. Together, these data suggest that IL-1R signaling regulates the susceptibility of the intestinal epithelia to damage caused by C. rodentium.

Distinct Roles for Nod2 Protein and Autocrine Interleukin-1β in Muramyl Dipeptide-induced Mitogen-activated Protein Kinase Activation and Cytokine Secretion in Human Macrophages

“…Interestingly, impaired IL-1R signaling can lead to increased disease severity in CD patients (17) and to worsening of dextran sulfate sodium and Citrobacter rodentium-induced mouse colitis (9,16). This contrasts with the simple interpretation that IL-1R signaling is associated with inflammatory disease.…”

“…The Nod2-induced IL-1␤ autocrine loop is of particular interest because the IL-1␤ pathway is relevant to inflammatory bowel disease as evidenced by: (i) CD association of loss-offunction polymorphisms in a region that includes NLRP3, a protein required for IL-1␤ processing (15), and (ii) association of decreased IL-1 receptor (IL-1R) signaling with more severe colitis in mouse and human studies (9,16,17). Given the importance of both Nod2 and IL-1R regulation for intestinal immune homeostasis (18) and the putative IL-1␤ contribution to Nod2-induced cytokine secretion, we sought to further define this contribution and determine the mechanism(s) of the IL-1␤ autocrine loop contribution to Nod2 responses.…”

Pre-treatment with IL-1β enhances the efficacy of MSC transplantation in DSS-induced colitis

“…15 However, growing evidence has indicated that IL-1b signaling supports colonic homeostasis and attenuated colonic inflammation. IL-1b signaling can protect mice from intestinal damage after Citrobacter rodentium infection 16 and from DSS-induced colitis. 17 Mice that are deficient in IL-1 receptor 1 (IL-1R1) exhibit exacerbated DSS-induced colitis, which is indicated by a higher disease activity index score and an increased mortality compared with wild-type mice.…”

NF-κB in the regulation of epithelial homeostasis and inflammation

“…One important aspect of MyD88 signaling that needs to be taken into account is that this adaptor is not only involved in TLR signaling but also in signaling induced by members of the IL-1 family of cytokines. These cytokines have been implicated in the regulation of intestinal inflammation, since mice that lack essential inflammasome components and therefore cannot produce biologically active IL-1β and IL-18 are hypersensitive to DSS-induced colitis [60][61][62][63] Although impaired responses to either IL-1β or IL-18 were shown to enhance susceptibility to DSS-induced colitis [64][65][66], IL-18 was identified as the crucial inflammasome-derived cytokine that protects mice from intestinal inflammation [61,63]. Even though the cellular target of IL-18 is not clear, these observations raise the possibility that the increased susceptibility of Myd88 -/-or IEC-specific NF-κB-deficient mice to DSS-induced colitis might, at least in part, be caused by impaired IL-18 signaling.…”