C-C Motif Ligand 20 (CCL20) and C-C Motif Chemokine Receptor 6 (CCR6) in Human Peripheral Blood Mononuclear Cells: Dysregulated in Ulcerative Colitis and a Potential Role for CCL20 in IL-1β Release.

Helene Skovdahl,Torunn Bruland,Atle Granlund,Berit Doseth,Tom Mollnes,Arne Sandvik,Jan Damås,Ann Østvik

doi:10.3390/ijms19103257

Abstract

The chemokine C-C motif ligand 20 (CCL20) is increased in the colonic mucosa during active inflammatory bowel disease (IBD) and can be found both in the epithelium and immune cells in the lamina propria. The present study investigated CCL20 and C-C motif Chemokine Receptor 6 (CCR6) in peripheral blood mononuclear cells (PBMCs) (n = 40) from IBD patients and healthy controls, to identify inductors of CCL20 release encountered in a local proinflammatory environment. CCL20 release from PBMCs was increased when activating TLR2/1 or NOD2, suggesting that CCL20 is part of a first line response to danger-associated molecular patterns also in immune cells. Overall, ulcerative colitis (UC) had a significantly stronger CCL20 release than Crohn’s disease (CD) (+242%, p < 0.01), indicating that the CCL20-CCR6 axis may be more involved in UC. The CCL20 receptor CCR6 is essential for the chemotactic function of CCL20. UC with active inflammation had significantly decreased CCR6 expression and a reduction in CCR6+ cells in circulation, indicating chemoattraction of CCR6+ cells from circulation towards peripheral tissues. We further examined CCL20 induced release of cytokines from PBMCs. Stimulation with CCL20 combined with TNF increased IL-1β release from PBMCs. By attracting additional immune cells, as well as inducing proinflammatory IL-1β release from immune cells, CCL20 may protract the inflammatory response in ulcerative colitis.

Highlights

Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn’s disease (CD), which share a disease pattern of intermittent inflammation of the gastrointestinal mucosa
C-C motif ligand 20 (CCL20) is increased in the mucosa of IBD patients [16,17,18] and CCL20 and Chemokine Receptor 6 (CCR6) have been identified as IBD susceptibility genes and are suggested as treatment targets in inflammatory conditions [19,20]
We found reduced CCR6 mRNA and CCR6+ cells in Peripheral blood mononuclear cells (PBMCs) from active UC compared to inactive UC, active CD and healthy controls

Summary

Introduction

Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn’s disease (CD), which share a disease pattern of intermittent inflammation of the gastrointestinal mucosa. The general view of the diseases is that inflammation occurs through an aberrant immune reaction to a normally tolerated gut flora in genetically susceptible individuals [1]. The balance between inflammatory response and tolerance towards gut flora depends on the proportions of regulatory and effector immune cells in the mucosa. As CCL20 recruits both regulatory T cells and Th17 cells, a change in CCL20 expression can potentially alter the balance between proinflammatory and regulatory responses [13,14,15]. CCL20 is increased in the mucosa of IBD patients [16,17,18] and CCL20 and CCR6 have been identified as IBD susceptibility genes and are suggested as treatment targets in inflammatory conditions [19,20]. We have previously found CCL20 expression in both the epithelium and in mononuclear cells in the lamina propria [18]

Objectives

Methods

Results

Conclusion