Dysregulation of the engulfment pathway in the gut fuels Inflammatory Bowel Disease

Suarez, K.; Lim, E.; Singh, S.; Pereira, M.; Joosen, L. P.; Ibeawuchi, S.-R.; Dunkel, Y.; Mittal, Y.; Ho, S. B.; Chattopadhyay, R.; Guma, M.; Boland, B. S.; Dulai, P. S.; Sandborn, W. J.; Ghosh, P.; Das, S.

doi:10.1101/280172

bioRxiv · 10.1101/280172

Dysregulation of the engulfment pathway in the gut fuels Inflammatory Bowel Disease

Suarez, K.·Lim, E.·Singh, S.·Pereira, M.·Joosen, L. P.·Ibeawuchi, S.-R.·Dunkel, Y.·Mittal, Y.·Ho, S. B.·Chattopadhyay, R.·Guma, M.·Boland, B. S.·Dulai, P. S.·Sandborn, W. J.·Ghosh, P.·Das, S.

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Abstract

BACKGROUND & AIMSLuminal dysbiosis is ubiquitous in inflammatory bowel disease (IBD), but how the microbes trigger pro-inflammatory cascades in the epithelial and phagocytic cells remains unknown. Here we investigated the role of the microbial sensor ELMO1 (Engulfment and Cell Motility Protein-1) in sensing and responding to IBD-associated microbes in the gut epithelium and in macrophages.\n\nMETHODSA stem cell-based technique is used to grow enteroids from WT and ELMO1-/-mice and from colonic biopsies of patients with IBD and subsequently differentiate them into enteroid-derived monolayers (EDMs) that mimic the gut epithelium/Gut in a dish. EDMs infected with IBD-associated invasive E. coli-LF82 were analyzed for bacterial internalization, cytokine production and monocyte-recruitment when co-cultured with monocytes.\n\nRESULTSExpression of ELMO1 is elevated in the colonic epithelium and in the inflammatory infiltrates within the lamina propria in IBD, higher expression correlated with elevated expression of pro-inflammatory cytokines, MCP-1 and TNF-. ELMO1-/-murine EDMs displayed a significant reduction of bacterial internalization through epithelial tight junctions and in MCP-1 production compared to WT mice. MCP-1 that is released from the epithelium recruited monocytes. Once recruited, macrophages required ELMO1 to engulf the bacteria and propagate a robust pro-inflammatory cytokine storm (TNF-).\n\nCONCLUSIONSELMO1 couples microbial-sensing to inflammation in both phagocytic and non-phagocytic host cells; it is required for the production of MCP-1 in the epithelium and TNF- in macrophages. Findings raise the possibility that upregulation of epithelial ELMO1 and the epithelial ELMO1[->]MCP-1 axis may serve as an early biomarker and therapeutic target, respectively, in IBD and other disorders of inflammation.

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Suarez, K., Lim, E., Singh, S., Pereira, M., Joosen, L. P., Ibeawuchi, S.-R., Dunkel, Y., Mittal, Y., Ho, S. B., Chattopadhyay, R., Guma, M., Boland, B. S., Dulai, P. S., Sandborn, W. J., Ghosh, P., Das, S.. 2018-03-12. Dysregulation of the engulfment pathway in the gut fuels Inflammatory Bowel Disease. https://doi.org/10.1101/280172

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