SUCNR1 Mediates the Priming Step of the Inflammasome in Intestinal Epithelial Cells: Relevance in Ulcerative Colitis.

Cristina Bauset,Maria D Barrachina,Lluis Lis-Lopez,Dulce C Macias-Ceja,Laura Gisbert-Ferrándiz,Francisco Navarro,Marta Seco-Cervera,Sara Calatayud,Dolores Ortiz-Masia,Jesús Cosín-Roger,Juan V Esplugues,Sandra Coll

doi:10.3390/biomedicines10030532

Abstract

Intestinal epithelial cells (IECs) constitute a defensive physical barrier in mucosal tissues and their disruption is involved in the etiopathogenesis of several inflammatory pathologies, such as Ulcerative Colitis (UC). Recently, the succinate receptor SUCNR1 was associated with the activation of inflammatory pathways in several cell types, but little is known about its role in IECs. We aimed to analyze the role of SUCNR1 in the inflammasome priming and its relevance in UC. Inflammatory and inflammasome markers and SUCNR1 were analyzed in HT29 cells treated with succinate and/or an inflammatory cocktail and transfected with SUCNR1 siRNA in a murine DSS model, and in intestinal resections from 15 UC and non-IBD patients. Results showed that this receptor mediated the inflammasome, priming both in vitro in HT29 cells and in vivo in a murine chronic DSS-colitis model. Moreover, SUNCR1 was also found to be involved in the activation of the inflammatory pathways NFкB and ERK pathways, even in basal conditions, since the transient knock-down of this receptor significantly reduced the constitutive levels of pERK-1/2 and pNFкB and impaired LPS-induced inflammation. Finally, UC patients showed a significant increase in the expression of SUCNR1 and several inflammasome components which correlated positively and significantly. Therefore, our results demonstrated a role for SUCNR1 in basal and stimulated inflammatory pathways in intestinal epithelial cells and suggested a pivotal role for this receptor in inflammasome activation in UC.

Highlights

IntroductionIntestinal epithelial cells (IECs) are pivotal cells in the maintenance of mucosal integrity
Introduction published maps and institutional affilIntestinal epithelial cells (IECs) are pivotal cells in the maintenance of mucosal integrity.They do so by forming a physical barrier, acting as sensors for damage- or pathogenassociated molecular patterns and regulating immune cells [1]
Significant reduction in the expression of NLRP3, IL1B, IL18 and ASC in siSUCNR1 cells treated with the cocktail or the combination compared with siRNA control cells (Figure 1c)

Summary

Introduction

Intestinal epithelial cells (IECs) are pivotal cells in the maintenance of mucosal integrity. They do so by forming a physical barrier, acting as sensors for damage- or pathogenassociated molecular patterns and regulating immune cells [1]. Bowel Disease (IBD) [3]. Ulcerative Colitis (UC) is a subtype of IBD characterized by a diffuse, continuous and chronic inflammation limited to the mucosa and submucosa layers of the colon. DSS, SUCNR1−/− vh and SUCNR1−/− DSS (n = 10 mice per group). At the end of the last cycle, on day 60, mice were properly handled and euthanized, and colon tissue samples were collected for further analysis

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