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Loss of intestinal integrity

The intestinal epithelium provides a mechanical barrier that prevents pathogens, antigens, and toxins from entering the body. The intestinal epithelial cells (IECs) that form this barrier are continuously turned over, and this process requires precise control and cytoskeletal rearrangement in order to preserve barrier function. Loss of epithelial integrity is associated with inflammatory bowel diseases (IBDs), such as Crohn’s disease and ulcerative colitis; however, the disease-associated pathways that drive IEC alteration are not completely understood.  Rocío López-Posadas and colleagues at University Hospital of Erlangen used a genome-wide approach to characterize the transcriptome of IECs from patients with IBD and identified disease-specific impairment in Rho-A signaling in patients with active IBD. Compared to those from control patients, IECs from the inflamed intestines of IBD patients exhibited cytosolic accumulation of Rho-A, reduction of Rho-A activation, and reduced expression the Rho-A prenylation enzyme GGTase-I. In a murine model, IEC-specific deletion of either Rhoa or the GGTase-I-encoding gene resulted in spontaneous development of chronic intestinal inflammation along with infiltration of CD4+ T cells and graulocytes. Moreover, cytoskeletal rearrangement and aberrant cell shedding were observed in these animals and led to loss of intestinal epithelial integrity. Activation of Rho-A in GGTase-I-deficient mice ameliorated mucosal damage and decreased expression of pro-inflammatory cytokines. Together, the results of this study identify loss of Rho-A signaling as a driver of IBD pathogenesis and suggest that restoration of this pathway has potential as a therapeutic strategy for IBD. The accompanying image shows GGTase-I staining (red) in IECs (EpCAM, green) in gut samples collected from a healthy individual (left), the inflamed region of a person with Crohn’s disease (middle), and an inflamed region of a person with ulcerative colitis (right). Note the reduction and altered localization of GGTase-I staining in the individuals with IBD. 

Published January 11, 2016, by Corinne Williams

Scientific Show StopperGastroenterology

Related articles

Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation
Rocío López-Posadas, … , Markus F. Neurath, Imke Atreya
Rocío López-Posadas, … , Markus F. Neurath, Imke Atreya
Published January 11, 2016
Citation Information: J Clin Invest. 2016;126(2):611-626. https://doi.org/10.1172/JCI80997.
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Research Article Gastroenterology

Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation

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Abstract

Although defects in intestinal barrier function are a key pathogenic factor in patients with inflammatory bowel diseases (IBDs), the molecular pathways driving disease-specific alterations of intestinal epithelial cells (IECs) are largely unknown. Here, we addressed this issue by characterizing the transcriptome of IECs from IBD patients using a genome-wide approach. We observed disease-specific alterations in IECs with markedly impaired Rho-A signaling in active IBD patients. Localization of epithelial Rho-A was shifted to the cytosol in IBDs, and inflammation was associated with suppressed Rho-A activation due to reduced expression of the Rho-A prenylation enzyme geranylgeranyltransferase-I (GGTase-I). Functionally, we found that mice with conditional loss of Rhoa or the gene encoding GGTase-I, Pggt1b, in IECs exhibit spontaneous chronic intestinal inflammation with accumulation of granulocytes and CD4+ T cells. This phenotype was associated with cytoskeleton rearrangement and aberrant cell shedding, ultimately leading to loss of epithelial integrity and subsequent inflammation. These findings uncover deficient prenylation of Rho-A as a key player in the pathogenesis of IBDs. As therapeutic triggering of Rho-A signaling suppressed intestinal inflammation in mice with GGTase-I–deficient IECs, our findings suggest new avenues for treatment of epithelial injury and mucosal inflammation in IBD patients.

Authors

Rocío López-Posadas, Christoph Becker, Claudia Günther, Stefan Tenzer, Kerstin Amann, Ulrike Billmeier, Raja Atreya, Gionata Fiorino, Stefania Vetrano, Silvio Danese, Arif B. Ekici, Stefan Wirtz, Veronika Thonn, Alastair J.M. Watson, Cord Brakebusch, Martin Bergö, Markus F. Neurath, Imke Atreya

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