Host engulfment pathway controls inflammation in inflammatory bowel disease

Ibrahim M. Sayed, Katherine Suarez, Eileen Lim, Sujay Singh, Matheus Pereira, Stella Rita Ibeawuchi, Gajanan Katkar, Ying Dunkel, Yash Mittal, Ranajoy Chattopadhyay, Monica Guma, Brigid S. Boland, Parambir S. Dulai, William J. Sandborn, Pradipta Ghosh, Soumita Das*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)3967-3988
Number of pages22
JournalFEBS Journal
Volume287
Issue number18
DOIs
StatePublished - Sep 1 2020
Externally publishedYes

Keywords

  • enteroid
  • epithelial-immune cell crosstalk
  • inflammatory bowel disease
  • microbial sensing and bacterial engulfment
  • monocyte chemoattractant protein 1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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