Host engulfment pathway controls inflammation in inflammatory bowel disease
| Autor: | Stella-Rita Ibeawuchi, Matheus Pereira, Ranajoy Chattopadhyay, Gajanan D. Katkar, Pradipta Ghosh, Eileen Lim, Sujay Singh, Brigid S. Boland, Soumita Das, William J. Sandborn, Monica Guma, Ying Dunkel, Yash Mittal, Parambir S. Dulai, Ibrahim M Sayed, Katherine Suarez |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine THP-1 Cells medicine.medical_treatment Crohn's Disease Medical Biochemistry and Metabolomics Inbred C57BL Biochemistry Inflammatory bowel disease Oral and gastrointestinal Mice 0302 clinical medicine enteroid 2.1 Biological and endogenous factors Aetiology Intestinal Mucosa Mice Knockout Adaptor Proteins epithelial-immune cell crosstalk Middle Aged Colitis Organoids medicine.anatomical_structure ELMO1 Cytokine 030220 oncology & carcinogenesis Host-Pathogen Interactions Cytokines Female Tumor necrosis factor alpha medicine.symptom Adult Biochemistry & Molecular Biology Knockout Inflammation Autoimmune Disease Article Medicinal and Biomolecular Chemistry Young Adult 03 medical and health sciences inflammatory bowel disease medicine Animals Humans Molecular Biology Adaptor Proteins Signal Transducing Aged Lamina propria business.industry Inflammatory and immune system Monocyte Signal Transducing monocyte chemoattractant protein 1 Cell Biology Inflammatory Bowel Diseases medicine.disease Epithelium Mice Inbred C57BL microbial sensing and bacterial engulfment 030104 developmental biology Gene Expression Regulation Immunology Citrobacter rodentium Biochemistry and Cell Biology Digestive Diseases business |
| Zdroj: | FEBS J The FEBS journal, vol 287, iss 18 |
| ISSN: | 1742-4658 1742-464X |
| DOI: | 10.1111/febs.15236 |
| Popis: | Chronic diseases, including inflammatory bowel disease (IBD) urgently need new biomarkers as a significant proportion of patients, do not respond to current medications. Inflammation is a common factor in these diseases, and microbial sensing in the intestinal tract is critical to initiate the inflammation. We have identified ELMO1 (engulfment and cell motility protein 1) as a microbial sensor in epithelial and phagocytic cells that turns on inflammatory signals. Using a stem cell-based 'gut-in-a-dish' coculture model, we studied the interactions between microbes, epithelium, and monocytes in the context of IBD. To mimic the invivo cell physiology, enteroid-derived monolayers (EDMs) were generated from the organoids isolated from WT and ELMO1-/- mice and colonic biopsies of IBD patients. The EDMs were infected with the IBD-associated microbes to monitor the inflammatory responses. ELMO1-depleted EDMs displayed a significant reduction in bacterial internalization, a decrease in pro-inflammatory cytokine productions and monocyte recruitment. The expression of ELMO1 is elevated in the colonic epithelium and in the inflammatory infiltrates within the lamina propria of IBD patients where the higher expression is positively correlated with the elevated expression of pro-inflammatory cytokines, MCP-1 and TNF-α. MCP-1 is released from the epithelium and recruits monocytes to the site of inflammation. Once recruited, monocytes require ELMO1 to engulf the bacteria and propagate a robust TNF-α storm. These findings highlight that the dysregulated epithelial ELMO1→MCP-1 axis can serve as an early biomarker in the diagnostics of IBD and other inflammatory disorders. |
| Databáze: | OpenAIRE |
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