IRE1α-driven inflammation promotes clearance of Citrobacter rodentium infection.
Lydia A SweetSharon K Kuss-DuerkopA Marijke Keestra-GounderPublished in: Infection and immunity (2021)
Endoplasmic reticulum (ER) stress is intimately linked with inflammation in response to pathogenic infections. ER stress occurs when cells experience a buildup of misfolded or unfolded protein during times of perturbation, such as infections, which facilitates the unfolded protein response (UPR). The UPR involves multiple host pathways in an attempt to re-establish homeostasis, which oftentimes leads to inflammation and cell death if unresolved. The UPR is activated to help resolve some bacterial infections, and the IRE1α pathway is especially critical in mediating inflammation. To understand the role of the IRE1α pathway of the UPR during enteric bacterial infection, we employed Citrobacter rodentium to study host-pathogen interactions in intestinal epithelial cells and the murine gastrointestinal (GI) tract. C. rodentium is an enteric mouse pathogen that is similar to the human pathogens enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC, respectively), which have limited small animal models. Here, we demonstrate that both C. rodentium and EPEC induced the UPR in intestinal epithelial cells. UPR induction during C. rodentium infection correlated with the onset of inflammation in bone marrow-derived macrophages (BMDMs). Our previous work implicated IRE1α and NOD1/2 in ER stress-induced inflammation, which we observed were also required for pro-inflammatory gene induction during C. rodentium infection. C. rodentium induced IRE1α-dependent inflammation in mice, and inhibiting IRE1α led to a dysregulated inflammatory response and delayed clearance of C. rodentium. This study demonstrates that ER stress aids inflammation and clearance of C. rodentium through a mechanism involving the IRE1α-NOD1/2 axis.
Keyphrases
- oxidative stress
- endoplasmic reticulum stress
- endoplasmic reticulum
- induced apoptosis
- escherichia coli
- inflammatory response
- stress induced
- diabetic rats
- signaling pathway
- type diabetes
- cell proliferation
- pseudomonas aeruginosa
- endothelial cells
- protein protein
- mesenchymal stem cells
- transcription factor
- genome wide
- staphylococcus aureus
- multidrug resistant
- antimicrobial resistance
- copy number