Gut Microbiota Species Can Provoke both Inflammatory and Tolerogenic Immune Responses in Human Dendritic Cells Mediated by Retinoic Acid Receptor Alpha Ligation.

Krisztian Bene,Nadiya Boyko,Eva Rajnavolgyi,Viktor O Petrov,Zsofia Varga

doi:10.3389/fimmu.2017.00427

Abstract

Dendritic cells are considered as the main coordinators of both mucosal and systemic immune responses, thus playing a determining role in shaping the outcome of effector cell responses. However, it is still uncovered how primary human monocyte-derived DC (moDC) populations drive the polarization of helper T (Th) cells in the presence of commensal bacteria harboring unique immunomodulatory properties. Furthermore, the individual members of the gut microbiota have the potential to modulate the outcome of immune responses and shape the immunogenicity of differentiating moDCs via the activation of retinoic acid receptor alpha (RARα). Here, we report that moDCs are able to mediate robust Th1 and Th17 responses upon stimulation by Escherichia coli Schaedler or Morganella morganii, while the probiotic Bacillus subtilis strain limits this effect. Moreover, physiological concentrations of all-trans retinoic acid (ATRA) are able to re-program the differentiation of moDCs resulting in altered gene expression profiles of the master transcription factors RARα and interferon regulatory factor 4, and concomitantly regulate the cell surface expression levels of CD1 proteins and also the mucosa-associated CD103 integrin to different directions. It was also demonstrated that the ATRA-conditioned moDCs exhibited enhanced pro-inflammatory cytokine secretion while reduced their co-stimulatory and antigen-presenting capacity thus reducing Th1 and presenting undetectable Th17 type responses against the tested microbiota strains. Importantly, these regulatory circuits could be prevented by the selective inhibition of RARα functionality. These results altogether demonstrate that selected commensal bacterial strains are able to drive strong effector immune responses by moDCs, while in the presence of ATRA, they support the development of both tolerogenic and inflammatory moDC in a RARα-dependent manner.

Highlights

The development and the metabolic activity of the human immune system critically depend on the amount and the diversity of the human microbiota acquired from the actual tissue microenvironment [1, 2]
We found that in the presence of 1 nM all-trans retinoic acid (ATRA), monocytes generated in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4 induced the differentiation of monocytes to monocyte-derived dendritic cell (DC) (moDC) within 2 days accompanied by the increasing expression levels of genes encoding the nuclear hormone receptor RXRα as well as its dimerization partners RARα and PPARγ in line with the aldehyde dehydrogenase-1 family member A2 (ALDH1A2)/retinaldehyde-dehydrogenase 2 (RALDH2) gene (Figure 1A) playing role in the regulation of retinoic acid production in moDCs
Murine models suggested that CD11b+ bone marrow-derived DCs cultured in the presence of GM-CSF and IL-4 express interferon regulatory factor 4 (IRF4) and regulate the cell surface expression of the major histocompatibility gene complex II (MHC class II), while IRF4 increases the antigen-presenting capacity of moDCs resulting in potent T helper cell priming [41]

Summary

Introduction

The development and the metabolic activity of the human immune system critically depend on the amount and the diversity of the human microbiota acquired from the actual tissue microenvironment [1, 2]. Our knowledge about the interplay of molecular interactions during diet involving vitamin A supplementation, and the presence of gut microbiota species in the course of an ongoing human immune system is still limited in both health and diseases. The uncontrolled disruption of the gut microbiota can be provoked by dysbiosis due to excessive hygiene conditions and/or the presence of antibiotics. This microbial perturbation may play role in the pathogenesis of chronic inflammatory and autoimmune diseases such as inflammatory bowel diseases (IBD), celiac disease, allergy, and metabolic and neurobehavioral diseases. In Crohn’s disease, the ratio of Proteobacteria could be increased [6], while the diversity and the fraction of Firmicutes in the gut microbiota are decreased [7]. The various effects of probiotic gut bacteria may prevent infection by pathogens such as the probiotic E. coli Nissle 1917 strain, which is able to inhibit the growth of enteropathogenic E. coli, which may serve as a safe strain in IBD treatment [10,11,12]

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