MTOR-Dependent Stimulation of IL20RA Orchestrates Immune Cell Trafficking through Lymphatic Endothelium in Patients with Crohn's Disease.

Federica Ungaro,Antonino Spinelli,Stefania Vetrano,Gaia Colasante,Luca Massimino,Salvatore Spanò,Silvia D’Alessio,Laurent Peyrin-Biroulet,Michele Carvello,Matteo Sacchi,Silvio Danese,Nicholas Valassina,Alberto Malesci,Valentina Garlatti

doi:10.3390/cells8080924

Abstract

Crohn’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 α (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.

Highlights

Crohn’s disease (CD), belonging to inflammatory bowel disease (IBD), is a chronic inflammatory condition that can affect different portions of the gastrointestinal tract [1]
To define the molecular signatures associated with CD lymphatic endothelial cells, human intestinal lymphatic endothelial cells (HILECs) were isolated either from inflamed ilea of patients with CD who underwent surgery (CD HILEC), or from healthy resection margins of ilea collected from patients with colorectal cancer
We found those related to glucocorticoid receptor (GCR), interleukin 6 (IL6), signaling pathway involved in platelet activation (SSPA), C-C chemokine receptor type 3 (CCR3), and

Summary

Introduction

Crohn’s disease (CD), belonging to inflammatory bowel disease (IBD), is a chronic inflammatory condition that can affect different portions of the gastrointestinal tract [1]. From a histological point of view, inflammation of the gut mucosa may affect all segments of the gastrointestinal. Cells 2019, 8, 924 tract, more commonly the terminal ileum and colon, with an asymmetrical, segmental, and transmural pattern. Patients may develop complications due to chronic inflammation, such as strictures, fistulas, or abscesses, leading to surgical resection of the complicated disease segment [1]. There is no cure for this disease, and current therapeutic strategies only aim at relieving symptoms, preventing complications and hampering the progressive course of the disease. Understanding the cellular and molecular mechanisms underlying CD etiopathogenesis may be of help for novel therapeutic strategies

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Results

Conclusion