Dendritic Cell-Specific Deletion of β-Catenin Results in Fewer Regulatory T-Cells without Exacerbating Autoimmune Collagen-Induced Arthritis.

C Henrique Alves,Wida Razawy,Adriana M C Mus,Patrick S Asmawidjaja,Inge Brouwers-Haspels,Julia L Ober-Blöbaum,Erik Lubberts,Marlieke Molendijk,Björn E Clausen

doi:10.1371/journal.pone.0142972

Abstract

Dendritic cells (DCs) are professional antigen presenting cells that have the dual ability to stimulate immunity and maintain tolerance. However, the signalling pathways mediating tolerogenic DC function in vivo remain largely unknown. The β-catenin pathway has been suggested to promote a regulatory DC phenotype. The aim of this study was to unravel the role of β-catenin signalling to control DC function in the autoimmune collagen-induced arthritis model (CIA). Deletion of β-catenin specifically in DCs was achieved by crossing conditional knockout mice with a CD11c-Cre transgenic mouse line. Bone marrow-derived DCs (BMDCs) were generated and used to study the maturation profile of these cells in response to a TLR2 or TLR4 ligand stimulation. CIA was induced by intra-dermal immunization with 100 μg chicken type II collagen in complete Freund’s adjuvant on days 0 and 21. CIA incidence and severity was monitored macroscopically and by histology. The T cell profile as well as their cytokine production were analysed by flow cytometry. Lack of β-catenin specifically in DCs did not affect the spontaneous, TLR2- or TLR4-induced maturation and activation of BMDCs or their cytokine production. Moreover, no effect on the incidence and severity of CIA was observed in mice lacking β-catenin in CD11c+ cells. A decreased frequency of splenic CD3+CD8+ T cells and of regulatory T cells (Tregs) (CD4+CD25highFoxP3+), but no changes in the frequency of splenic Th17 (CCR6+CXCR3-CCR4+), Th2 (CCR6-CXCR3-CCR4+) and Th1 (CCR6-CXCR3+CCR4-) cells were observed in these mice under CIA condition. Furthermore, the expression of IL-17A, IL-17F, IL-22, IL-4 or IFNγ was also not affected. Our data indicate that ablation of β-catenin expression in DCs did not alter the course and severity of CIA. We conclude that although deletion of β-catenin resulted in a lower frequency of Tregs, this decrease was not sufficient to aggravate the onset and severity of CIA.

Highlights

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and destruction of cartilage and bone [1, 2]
In the β-catDEL group, LPS (Fig 1A and 1B) or M. tuberculosis (MTB) (Fig 1C and 1D) stimulation both failed to trigger any expression of β-catenin. These data indicate efficient Cremediated deletion of β-catenin in immature and mature β-catDEL Bone marrow-derived DCs (BMDCs) and that TLR2- or TLR4-induced maturation of BMDCs by MTB or LPS respectively leads to an upregulation of β-catenin, which is in line with previous studies [15]
We hypothesize that the dissimilar consequences of deletion of β-catenin in CD11c+ for the development of inflammatory bowel disease (IBD), EAE and collagen-induced arthritis (CIA) might at least in part be explained by the local tissue expression of wnt proteins and the dendritic cells (DCs)-intrinsic gene machinery that lead to differential activation of wnt target genes in DCs present in each target tissue

Summary

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and destruction of cartilage and bone [1, 2]. Development of the disease is mediated by both adaptive and innate effects of DCs, namely priming of autoreactive T cells and induction of local inflammation via soluble mediators such as TNF [6] Owing to their regulatory function DCs might have therapeutic potential to treat RA, since administration of semimature or tolerogenic DCs can inhibit collagen-induced arthritis (CIA) [7,8,9]. In this context, it is crucial to dissect the molecular pathways that regulate the balance between pro-inflammatory and tolerogenic functions of DCs. It has previously been suggested that β-catenin, an essential component of the canonical wingless (wnt) pathway and widely expressed in immune cells including DCs, plays an important role in the switch between a tolerogenic and an immunogenic DC phenotype [10, 11]. This leads to the cytoplasmic accumulation of βcatenin and its translocation to the nucleus in order to interact with the T cell-specific transcription factor (TCF) and lymphoid enhancer-binding factor (LEF) that regulate the expression of wnt target genes [10]

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