Host engulfment pathway controls inflammation in inflammatory bowel disease

FEBS J. 2020 Sep;287(18):3967-3988. doi: 10.1111/febs.15236. Epub 2020 Feb 20.

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.

Keywords: enteroid; epithelial-immune cell crosstalk; inflammatory bowel disease; microbial sensing and bacterial engulfment; monocyte chemoattractant protein 1.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adult
  • Aged
  • Animals
  • Citrobacter rodentium / physiology
  • Colitis / genetics
  • Colitis / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Female
  • Gene Expression Regulation
  • Host-Pathogen Interactions
  • Humans
  • Inflammation / genetics*
  • Inflammation / metabolism
  • Inflammatory Bowel Diseases / genetics*
  • Inflammatory Bowel Diseases / metabolism
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / microbiology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Organoids / metabolism
  • THP-1 Cells
  • Young Adult

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytokines
  • ELMO1 protein, mouse