Abstract

Host engulfment pathway controls inflammation in Inflammatory Bowel Disease

Sayed IM1,2, Suarez K1, Lim E1, Singh S1, Pereira M1, Ibeawuchi SR1, Katkar G3, Dunkel Y4, Mittal Y4, Chattopadhyay R3, Guma M4, Boland BS4, Dulai PS4, Sandborn WJ4, Ghosh P4,3, Das S1. FEBS J. 2020 Jan 30. doi: 10.1111/febs.15236. [Epub ahead of print]

 
     

Author information

1 Department of Pathology, University of California San Diego, San Diego, USA.

2 Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Egypt.

3 Department of Cellular & Molecular Medicine, University of California San Diego, San Diego, USA.

4 Department of Medicine, University of California San Diego, San Diego, USA.

Abstract

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 in-vivo 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 inflammatoryinfiltrates 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.

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