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

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.

DNA methylome and transcriptome profiling reveal key electrophysiology and immune dysregulation in hypertrophic cardiomyopathy

“…According to the enriched KEGG and GO pathways, the DEGs were involved in biological processes related to immune response, myocardial growth and development, cardiac conduction, and electrophysiology. The immune response-related genes included ESR1 [ 48 , 49 ], ITLN1 [ 50 , 51 ], AHNAK2 [ 52 , 53 ], FFAR2 [ 54–56 ], IL20RA [ 57 , 58 ], and VEGFC [ 59 , 60 ]. The myocardial growth and development-related genes included ESR1 [ 61 , 62 ], ITLN1 [ 63 , 64 ], EYA2 [ 65 , 66 ], VEGFC [ 67 ], and DCHS2 [ 68 ].…”

A Bayesian hierarchically structured prior for rare‐variant association testing

“…Rs8178555 resides in Interleukin 10 Receptor Subunit Beta ( IL10RB ), which has been shown to also contain a common variant that is 2519 bp apart from rs8178555 and is protective against early‐onset Crohn's disease (Moran et al, 2013). Rs1167848 resides in Interleukin 20 Receptor Subunit Alpha ( IL20RA ), which has been shown to be associated with the resolution of chronic inflammation in patients with Crohn's disease (Ungaro et al, 2019). Rs3218256 resides in Interleukin 2 Receptor Subunit Beta ( IL2RB ), which has plausible association with Crohn's disease in the Tunisian population (Bouzid et al, 2013).…”

Crohn’s disease as the intestinal manifestation of pan-lymphatic dysfunction: An exploratory proposal based on basic and clinical data

“…The VEGFR3-phosphoinositide 3-kinase (PI3K) signaling pathway is another important regulatory axis in lymphatic vasculature development, and activation of the PI3K-AKT-mammalian target of rapamycin (mTOR) pathway is involved in CD pathogenesis[ 62 ]. The mTOR signaling pathway plays a pivotal role in CD[ 63 ] and a recent study revealed its active involvement in intestinal lymphatic function through effects on leukocyte trafficking in patients with CD[ 64 ]. Additionally, angiopoietin-TIE signaling contributes to whole-body lymphatic vessel development and is important for mesenteric lymphatic development and maintenance[ 65 , 66 ].…”