HOIL1 Regulates Group 3 Innate Lymphoid Cells in the Colon and Protects against Systemic Dissemination, Colonic Ulceration, and Lethality from Citrobacter rodentium Infection.
Victoria L HartleyArwa M QaqishMatthew J WoodBrian T StudnickaKazuhiro IwaiTa-Chiang LiuDonna A MacDuffPublished in: Journal of immunology (Baltimore, Md. : 1950) (2023)
Heme-oxidized IRP2 ubiquitin ligase-1 (HOIL1)-deficient patients experience chronic intestinal inflammation and diarrhea as well as increased susceptibility to bacterial infections. HOIL1 is a component of the linear ubiquitin chain assembly complex that regulates immune signaling pathways, including NF-κB-activating pathways. We have shown previously that HOIL1 is essential for survival following Citrobacter rodentium gastrointestinal infection of mice, but the mechanism of protection by HOIL1 was not examined. C. rodentium is an important murine model for human attaching and effacing pathogens, enteropathogenic and enterohemorrhagic Escherichia coli that cause diarrhea and foodborne illnesses and lead to severe disease in children and immunocompromised individuals. In this study, we found that C. rodentium infection resulted in severe colitis and dissemination of C. rodentium to systemic organs in HOIL1-deficient mice. HOIL1 was important in the innate immune response to limit early replication and dissemination of C. rodentium. Using bone marrow chimeras and cell type-specific knockout mice, we found that HOIL1 functioned in radiation-resistant cells and partly in radiation-sensitive cells and in myeloid cells to limit disease, but it was dispensable in intestinal epithelial cells. HOIL1 deficiency significantly impaired the expansion of group 3 innate lymphoid cells and their production of IL-22 during C. rodentium infection. Understanding the role HOIL1 plays in type 3 inflammation and in limiting the pathogenesis of attaching and effacing lesion-forming bacteria will provide further insight into the innate immune response to gastrointestinal pathogens and inflammatory disorders.
Keyphrases
- induced apoptosis
- signaling pathway
- cell cycle arrest
- oxidative stress
- bone marrow
- escherichia coli
- innate immune
- type diabetes
- early onset
- acute myeloid leukemia
- ejection fraction
- pi k akt
- immune response
- dendritic cells
- epithelial mesenchymal transition
- extracorporeal membrane oxygenation
- toll like receptor
- acute respiratory distress syndrome
- radiation induced
- smoking cessation
- mechanical ventilation
- inflammatory response
- insulin resistance
- high fat diet induced
- lps induced