Affective disorders (AD) including major depressive disorder (MDD) and bipolar disorder (BD) are common mood disorders associated with increased disability and poor health outcomes. Altered immune responses characterized by increased serum levels of pro-inflammatory cytokines and neuroinflammation are common findings in patients with AD and in corresponding animal models. Dendritic cells (DCs) represent a heterogeneous population of myeloid cells that orchestrate innate and adaptive immune responses and self-tolerance. Upon sensing exogenous and endogenous danger signals, mature DCs secrete proinflammatory factors, acquire migratory and antigen presenting capacities and thus contribute to neuroinflammation in trauma, autoimmunity, and neurodegenerative diseases. However, little is known about the involvement of DCs in the pathogenesis of AD. In this review, we summarize the current knowledge on DCs in peripheral immune responses and neuroinflammation in MDD and BD. In addition, we consider the impact of DCs on neuroinflammation and behavior in animal models of AD. Finally, we will discuss therapeutic perspectives targeting DCs and their effector molecules in mood disorders.

Contact hypersensitivity (CHS) is an established animal model for allergic contact dermatitis. Dendritic cells (DCs) play an important role in the sensitization phase of CHS by initiating T cell responses to topically applied haptens. The cannabinoid receptors 1 (CB1) and 2 (CB2) modulate DC functions and inflammatory skin responses, but their influence on the capacity of haptenized DCs to induce CHS is still unknown. We found lower CHS responses to 2,4-dinitro-1-fluorobenzene (DNFB) in wild type (WT) mice after adoptive transfer of haptenized Cnr2^−/− and Cnr1^−/−/Cnr2^−/− bone marrow (BM) DCs as compared to transfer of WT DCs. In contrast, induction of CHS was not affected in WT recipients after transfer of Cnr1^−/− DCs. In vitro stimulated Cnr2^−/− DCs showed lower CCR7 and CXCR4 expression when compared to WT cells, while in vitro migration towards the chemokine ligands was not affected by CB2. Upregulation of MHC class II and co-stimulatory molecules was also reduced in Cnr2^−/− DCs. This study demonstrates that CB2 modulates the maturation phenotype of DCs but not their chemotactic capacities in vitro. These findings and the fact that CHS responses mediated by Cnr2^−/− DCs are reduced suggest that CB2 is a promising target for the treatment of inflammatory skin conditions.

Restoring peripheral immune tolerance is crucial for addressing autoimmune diseases. An ancient mechanism in maintaining the balance between inflammation and tolerance is the ratio of extracellular ATP (exATP) and adenosine. Our previous research demonstrated the effectiveness of small spleen peptides (SSPs) in inhibiting psoriatic arthritis progression, even in the presence of the pro-inflammatory cytokine TNFα, by transforming dendritic cells (DCs) into tolerogenic cells and fostering regulatory Foxp3⁺ Treg cells. Here, we identified thymosins as the primary constituents of SSPs, but recombinant thymosin peptides were less efficient in inhibiting arthritis than SSPs. Since Tβ4 is an ecto-ATPase-binding protein, we hypothesized that SSPs regulate exATP profiles. Real-time investigation of exATP levels in DCs revealed that tolerogenic stimulation led to robust de novo exATP synthesis followed by significant degradation, while immunogenic stimulation resulted in a less pronounced increase in exATP and less effective degradation. These contrasting exATP profiles were crucial in determining whether DCs entered an inflammatory or tolerogenic state, highlighting the significance of SSPs as natural regulators of peripheral immunological tolerance, with potential therapeutic benefits for autoimmune diseases. Finally, we demonstrated that the tolerogenic phenotype of SSPs is mainly influenced by adenosine receptors, and in vivo administration of SSPs inhibits psoriatic skin inflammation.