mTOR-Dependent Stimulation of <i>IL20RA</i> Orchestrates Immune Cell Trafficking through Lymphatic Endothelium in Patients with Crohn’s Disease

Cells. 2019;8(8):924 DOI 10.3390/cells8080924

 

Journal Homepage

Journal Title: Cells

ISSN: 2073-4409 (Online)

Publisher: MDPI AG

LCC Subject Category: Science: Biology (General)

Country of publisher: Switzerland

Language of fulltext: English

Full-text formats available: PDF, HTML

 

AUTHORS


Federica Ungaro (IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy)

Valentina Garlatti (Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy)

Luca Massimino (Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy)

Antonino Spinelli (Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy)

Michele Carvello (Colon and Rectal Surgery Unit, Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy)

Matteo Sacchi (Colon and Rectal Surgery Unit, Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy)

Salvatore Spanò (IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy)

Gaia Colasante (Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy)

Nicholas Valassina (Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy)

Stefania Vetrano (IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy)

Alberto Malesci (Department of Medical Biotechnologies and Translational Medicine, University of Milan, 200129 Milan, Italy)

Laurent Peyrin-Biroulet (Inserm Ngere and Nancy University Hospital, Lorraine University, 54500 Vandoeuvre-lès-Nancy, France)

Silvio Danese (IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy)

Silvia D’Alessio (IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy)

EDITORIAL INFORMATION

Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 11 weeks

 

Abstract | Full Text

Crohn&#8217;s disease (CD) is a chronic inflammatory condition that can affect different portions of the gastrointestinal tract. Lymphatic drainage was demonstrated to be dysfunctional in CD pathogenesis, ultimately causing the failure of the resolution of intestinal inflammation. To investigate the molecular mechanisms underlying these dysfunctions, we isolated human intestinal lymphatic endothelial cells (HILECs) from surgical specimens of patients undergoing resection for complicated CD (CD HILEC) and from a disease-free margin of surgical specimens of patients undergoing resection for cancer (healthy HILEC). Both cell types underwent transcriptomic profiling, and their barrier functionality was tested using a transwell-based co-culture system between HILEC and lamina propria mononuclear cells (LPMCs). Results showed CD HILEC displayed a peculiar transcriptomic signature that highlighted mTOR signaling as an orchestrator of leukocyte trafficking through the lymphatic barrier of CD patients. Moreover, we demonstrated that LPMC transmigration through the lymphatic endothelium of patients with CD depends on the capability of mTOR to trigger interleukin 20 receptor subunit &#945; (IL20RA)-mediated intracellular signaling. Conclusively, our study suggests that leukocyte trafficking through the intestinal lymphatic microvasculature can be controlled by modulating IL20RA, thus leading to the resolution of chronic inflammation in patients with CD.