Molecular mechanisms of Rac1-mediated regulation of epithelial integrity in the inflamed gut
Final Report Abstract
Inflammatory Bowel Diseases (IBD) describe a group of disorders, including Crohn’s disease (CD) and Ulcerative Colitis (UC), characterized by a chronic and relapsing inflammation of the gastrointestinal tract. Affecting a rather young population, chronic occurrence of inflammatory flares lead to a substantial loss of quality of life for IBD patients, entailing an important socioeconomic impact. Despite an intensive scientific effort during the last decades, our understanding of the molecular pathogenesis underlying IBD remains incomplete. Due to a significant number of therapy-refractory patients and undesirable side effects of pharmacotherapy, there is a well-recognized need for the identification of innovative and disease-specific therapeutic target molecules within the inflamed tissue of IBD patients. The maintenance of epithelial barrier function is a key player for intestinal tissue homeostasis. Epithelial leakage is associated with the development of chronic intestinal inflammation, and even postulated as primary mechanisms in IBD pathogenesis. We believe that the understanding of epithelial barrier function in the gut and epithelial restoration could ultimately be translated into the clinical practice for the benefit of IBD patients. In this context, we previously demonstrated that regulation of small GTPases via post-translational prenylation represents a deciding factor for epithelial homeostasis in gut. In the present project, we have focused on the role of single prenylated proteins in this context, and more specifically, on RAC1. According to the literature, our data demonstrated that RAC1-mediated cytoskeleton dynamics controls epithelial integrity in the gut. The novelty of our study lies on the fact that epithelial changes in RAC1-deficient epithelium are triggered exclusively by cell intrinsic phenomena, causing disturbances of cell shedding and resulting in intestinal inflammation and destruction of tissue architecture. Together, our data highlight RAC1 as a GGTase-target contributing to epithelial integrity and intestinal homeostasis. Translationally, our study revealed a potential correlation between alteration of physiological cell shedding and epithelial RAC1 pathway and intestinal inflammation in IBD. These findings have been summarized in our publication entitled “Epithelial RAC1-dependent cytoskeleton dynamics controls cell mechanics, cell shedding and barrier integrity in intestinal inflammation”, which has been recently accepted for publication in Gut, a reference journal in the context of gastroenterology research. The scientific importance of this publication is also highlighted by the recent commentary published in the same journal, where the contribution of epithelial RAC1 in different niches are discussed. Our data provide a solid backbone for the assumption that modulation of RAC1 function within intestinal epithelium can pave the way to the identification of biomarkers for diagnosis, prediction and/or prevention of flares in IBD, and be exploited for epithelial restoration for the benefit of those patients. Improving the clinical management of IBD patients would then have an important impact on economy and society
Publications
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An Intravital Microscopy-Based Approach to Assess Intestinal Permeability and Epithelial Cell Shedding Performance. Journal of Visualized Experiments(166).
Martínez-Sánchez, Luz DC.; Pradhan, Rashmita; Ngo, Phuong A.; Erkert, Lena; Becker, Lukas S.; Watson, Alastair J.; Atreya, Imke; Neurath, Markus F. & López-Posadas, Rocío
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Rho GTPases as Key Molecular Players within Intestinal Mucosa and GI Diseases. Cells, 10(1), 66.
Pradhan, Rashmita; Ngo, Phuong A.; Martínez-Sánchez, Luz d. C.; Neurath, Markus F. & López-Posadas, Rocío
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Epithelial RAC1-dependent cytoskeleton dynamics controls cell mechanics, cell shedding and barrier integrity in intestinal inflammation. Gut, 72(2), 275-294.
Martínez-Sánchez, Luz del Carmen; Ngo, Phuong Anh; Pradhan, Rashmita; Becker, Lukas-Sebastian; Boehringer, David; Soteriou, Despina; Kubankova, Marketa; Schweitzer, Christine; Koch, Tatyana; Thonn, Veronika; Erkert, Lena; Stolzer, Iris; Günther, Claudia; Becker, Christoph; Weigmann, Benno; Klewer, Monika; Daniel, Christoph; Amann, Kerstin; Tenzer, Stefan ... & López-Posadas, Rocío
