Abstract
The dual potential to promote tolerance or inflammation to self-antigens makes dendritic cells (DCs) fundamental players in autoimmunity. Previous results have shown that stimulation of dopamine receptor D5 (DRD5) in DCs potentiates their inflammatory behaviour, favouring the development of experimental autoimmune encephalomyelitis (EAE). Here, we aimed to decipher the underlying mechanism and to test its relevance in multiple sclerosis (MS) patients. Our data shows that DRD5-deficiency confined to DCs in EAE mice resulted in reduced frequencies of CD4+ T-cell subsets with inflammatory potential in the central nervous system, including not only Th1 and Th17 cells but also granulocyte-macrophage colony-stimulating factor producers. Importantly, ex vivo depletion of dopamine from DCs resulted in a dramatic reduction of EAE severity, highlighting the relevance of an autocrine loop promoting inflammation in vivo. Mechanistic analyses indicated that DRD5-signalling in both mouse DCs and human monocytes involves the attenuation of signal transducer and activator of transcription 3-activation, a transcription factor that limits the production of the inflammatory cytokines interleukin (IL)-12 and IL-23. Furthermore, we found an exacerbated expression of all dopamine receptors in peripheral blood pro-inflammatory monocytes obtained from MS patients. These findings illustrate a novel mechanism by which myeloid antigen-presenting cells may trigger the onset of their inflammatory behaviour promoting the development of autoimmunity.
Highlights
T-cell mediated immunity can respond to a huge variety of foreign and self-antigens as a result of a wide repertoire of T-cell receptors generated by genomic recombination
Similar to most reports analysing the coupling of dopamine receptor D5 (DRD5) in different cell types [46], our results show here that DRD5-stimulation in dendritic cells (DCs) was coupled with cAMP production (Figure S1 in Supplementary Material)
To evaluate the role of DRD5-signalling confined to DCs in the development of EAE, we first performed a set of adoptive transfer experiments in which WT or DRD5KO DCs were loaded ex vivo with the autoantigen associated with EAE, a peptide derived from myelin oligodendrocyte glycoprotein (MOG), and transferred into WT recipients in which EAE was induced
Summary
T-cell mediated immunity can respond to a huge variety of foreign and self-antigens as a result of a wide repertoire of T-cell receptors generated by genomic recombination. By inducing the expression of anti-inflammatory mediators, such as IL-10, TGF-β, and retinaldehyde dehydrogenase, the activation of β-catenin has been described to play a pivotal role in the acquisition of the tolerogenic potential by DCs [8, 9]. Another key regulator of DCs behaviour is the transcription factor signal transducer and activator of transcription 3 (STAT3), which upon phosphorylation inhibits the NF-κB-mediated induction of IL-12 and IL-23, attenuating the inflammatory potential of these cells [10, 11]
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