Host engulfment pathway controls inflammation in inflammatory bowel disease.
Ibrahim M SayedKatherine SuarezEileen LimSujay SinghMatheus PereiraStella-Rita IbeawuchiGajanan KatkarYing DunkelYash MittalRanajoy ChattopadhyayMonica GumaBrigid S BolandParambir S DulaiWilliam J SandbornPradipta GhoshSoumita DasPublished in: The FEBS journal (2020)
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 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.
Keyphrases
- oxidative stress
- end stage renal disease
- poor prognosis
- ejection fraction
- ulcerative colitis
- stem cells
- chronic kidney disease
- dendritic cells
- prognostic factors
- rheumatoid arthritis
- induced apoptosis
- type diabetes
- peritoneal dialysis
- cell therapy
- escherichia coli
- immune response
- metabolic syndrome
- microbial community
- bone marrow
- long non coding rna
- adipose tissue
- signaling pathway
- patient reported outcomes
- mesenchymal stem cells
- binding protein
- endothelial cells
- amino acid
- anti inflammatory
- candida albicans
- solid state