Irgm1-deficiency leads to myeloid dysfunction in colon lamina propria and susceptibility to the intestinal pathogen Citrobacter rodentium
| العنوان: | Irgm1-deficiency leads to myeloid dysfunction in colon lamina propria and susceptibility to the intestinal pathogen Citrobacter rodentium |
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| المؤلفون: | Hsin-I Huang, Viviana Cantillana, Ajay S. Gulati, Gregory A. Taylor, Gianna E. Hammer, Mark L. Jewell, Allison R. Rogala, Anne F. Buckley, Nourhan Youssef, Alexi A. Schoenborn, Bruce A. Vallance, Carl G. Feng, Brian E. Fee |
| المصدر: | PLoS Pathogens PLoS Pathogens, Vol 16, Iss 5, p e1008553 (2020) |
| بيانات النشر: | Public Library of Science, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Apoptosis, Inflammatory bowel disease, Monocytes, Cell-Mediated Immunity, White Blood Cells, Mice, Animal Cells, Citrobacter rodentium, Medicine and Health Sciences, Biology (General), Pathogen, Immune Response, Mice, Knockout, 0303 health sciences, Cell Death, 030302 biochemistry & molecular biology, Enterobacteriaceae Infections, medicine.anatomical_structure, Cell Processes, IRGM, medicine.symptom, Cellular Types, Anatomy, Research Article, QH301-705.5, Colon, Immune Cells, Immunology, Inflammation, Bone Marrow Cells, Biology, Microbiology, digestive system, 03 medical and health sciences, Immune system, Immunity, GTP-Binding Proteins, Virology, Genetics, medicine, Animals, T Helper Cells, Molecular Biology, 030304 developmental biology, Lamina propria, Blood Cells, Mucous Membrane, Macrophages, Biology and Life Sciences, Cell Biology, RC581-607, medicine.disease, Inflammatory Bowel Diseases, Gastrointestinal Tract, Parasitology, Immunologic diseases. Allergy, Digestive System |
| الوصف: | IRGM and its mouse orthologue Irgm1 are dynamin-like proteins that regulate vesicular remodeling, intracellular microbial killing, and pathogen immunity. IRGM dysfunction is linked to inflammatory bowel disease (IBD), and while it is thought that defective intracellular killing of microbes underscores IBD susceptibility, studies have yet to address how IRGM/Irgm1 regulates immunity to microbes relevant to intestinal inflammation. Here we find that loss of Irgm1 confers marked susceptibility to Citrobacter rodentium, a noninvasive intestinal pathogen that models inflammatory responses to intestinal bacteria. Irgm1-deficient mice fail to control C. rodentium outgrowth in the intestine, leading to systemic pathogen spread and host mortality. Surprisingly, susceptibility due to loss of Irgm1 function was not linked to defective intracellular killing of C. rodentium or exaggerated inflammation, but was instead linked to failure to remodel specific colon lamina propria (C-LP) myeloid cells that expand in response to C. rodentium infection and are essential for C. rodentium immunity. Defective immune remodeling was most striking in C-LP monocytes, which were successfully recruited to the infected C-LP, but subsequently underwent apoptosis. Apoptotic susceptibility was induced by C. rodentium infection and was specific to this setting of pathogen infection, and was not apparent in other settings of intestinal inflammation. These studies reveal a novel role for Irgm1 in host defense and suggest that deficiencies in survival and remodeling of C-LP myeloid cells that control inflammatory intestinal bacteria may underpin IBD pathogenesis linked to IRGM dysfunction. Author summary Intestinal macrophages are seeded by peripheral monocytes that enter the intestine and mature into an essential component of immune defense. While this process is shaped by intestinal bacteria, the mechanisms that regulate the process, and their roles in host defense to enteric pathogens are poorly defined. We find that Irgm1 –the orthologue of the human Crohn’s disease resistance gene, IRGM–is required for monocyte/macrophage remodeling in response to the gram-negative enteric pathogen Citrobacter rodentium, with absence of Irgm1 leading to systemic spread of the bacterium and host mortality. Failure to remodel colonic monocytes/macrophages was due to a key requirement for Irgm1 in colon-infiltrating monocytes, which underwent dramatically high rates of cell death, specifically during the setting of enteric bacterial infection. While Irgm1/IRGM proteins are well appreciated for their role in regulating intracellular bacterial killing, our results expand the paradigm for Irgm1/IRGM-mediated host defense by demonstrating an essential function for Irgm1/IRGM to control the survival and population remodeling of monocytes and macrophages that expand during enteric infection and defend against pathogenic bacteria. These findings have significant implications for the genesis of Crohn’s disease in individuals that carry IRGM variants. |
| اللغة: | English |
| تدمد: | 1553-7374 1553-7366 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3af7f36646c3b434a7bc25c59c9b38cc http://europepmc.org/articles/PMC7274479 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....3af7f36646c3b434a7bc25c59c9b38cc |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15537374 15537366 |
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