α-MSH-Stimulated Tolerogenic Dendritic Cells Induce Functional Regulatory T Cells and Ameliorate Ongoing Skin Inflammation

Abstract

The neuropeptide α-melanocyte-stimulating hormone (α-MSH) is a well-known mediator of skin pigmentation. More recently, it has been shown that α-MSH also exerts a strong anti-inflammatory and immunosuppressive activity. To elucidate the mechanisms underlying α-MSH-induced immunosuppression, we investigated whether α-MSH affects dendritic cell/T cell communication, as especially this interaction has an important role in the regulation of immune responses. Here, we show that α-MSH, by binding to MC-1R, induced tolerogenic dendritic cells, which were capable of expanding CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) in vitro, as well as in vivo. Notably, those α-MSH-induced Tregs were functional as they efficiently inhibited cutaneous contact allergy and ongoing psoriasis-like skin inflammation in mice. Furthermore, α-MSH induced tolerogenic dendritic cells capable of generating functional Tregs in human blood. Interestingly, human Tregs expanded via α-MSH-stimulated dendritic cells suppressed the proliferation and cytokine secretion of pathogenic T-helper-17 (Th17) cells from individuals with psoriasis. Taken together, these data indicate that α-MSH induced immunosuppressive Tregs in vitro and in vivo, which inhibited disease progression in a mouse model of psoriasis-like skin inflammation and suppressed the activation and proliferation of effector T cells from subjects with psoriasis.

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

“…More recently, it has been shown that α-MSH also exerts a strong anti-inflammatory and immunosuppressive activity. Analysis of α-MSH effects on DCs revealed that α-MSH, by binding to MC-1R, induced regDCs, which were capable of expanding CD4 + CD25 + Foxp3 + regulatory T cells in vitro, as well as in vivo [91]. Notably, α-MSH induced regDCs were capable of generating functional Tregs in human blood.…”

“…Notably, α-MSH induced regDCs were capable of generating functional Tregs in human blood. Interestingly, human Tregs expanded via α-MSH-stimulated DCs suppressed the proliferation and cytokine secretion of T-helper-17 (Th17) cells [91]. As α-melanocyte-stimulating hormone is a ligand for the melanocortin 1 receptor (MC1R), which expressed on and play a role in malignant cell function through the Wnt/β-catenin pathway [92], its role in formation and action of tumorassociated regDCs should be further investigated.…”

Melanocortin-1 receptor activation is neuroprotective in mouse models of neuroinflammatory disease

“…The neuropeptide -melanocyte-stimulating hormone (-MSH) is a known mediator of skin pigmentation, but it also acts as potent immunomodulator capable of expanding thymic-derived and peripherally induced Treg, which inhibit the proliferation of psoriatic mouse as well as human Th1 and Th17 cells (14). The biologic effects of -MSH are mediated by binding to one of five G-protein-coupled melanocortin receptors (termed Mc1r-Mc5r) (15,16).…”

Protein Kinase C Inhibitor Generates Stable Human Tolerogenic Dendritic Cells

“…Human tDCs can be cultured in vitro from DC precursors using different compounds (7,18). For this purpose, anti-inflammatory cytokines such as and TGF-b (22)(23)(24), vitamin D 3 (Vit D 3 ) (25)(26)(27)(28), neuropeptides, including vasoactive intestinal peptide (17,29,30) and a-melanocyte-stimulating hormone (31), and anti-inflammatory/immunosuppressive drugs such as dexamethasone (Dexa) (28,32,33) and rapamycin (Rapa) (34)(35)(36) are often employed. However, the compound most suitable for clinical application remains undefined from the viewpoint of tolerogenic potential, stability, and capacity for migration toward secondary lymphoid organs, that is, the area where immune responses occur (37)(38)(39).…”