Human skin CD141⁺ dendritic cells regulate cutaneous immunity via the neuropeptide urocortin 2

Skin immune homeostasis is a multi-faceted process where dermal dendritic cells (DDCs) are key in orchestrating responses to environmental stressors. We have previously identified CD141⁺CD14⁺ DDCs as a skin-resident immunoregulatory population that is vitamin-D₃ (VitD3) inducible from monocyte-derived DCs (moDCs), termed CD141^hi VitD3 moDCs. We demonstrate that CD141⁺ DDCs and CD141^hi VitD3 moDCs share key immunological features including cell surface markers, reduced T cell stimulation, IL-10 production, and a common transcriptomic signature. Bioinformatic analysis identified the neuroactive ligand receptor pathway and the neuropeptide, urocortin 2 (UCN2), as a potential immunoregulatory candidate molecule. Incubation with VitD3 upregulated UCN2 in CD141⁺ DCs and UVB irradiation induced UCN2 in CD141⁺ DCs in healthy skin in vivo. Notably, CD141⁺ DDC generation of suppressive Tregs was dependent upon the UCN2 pathway as in vivo administration of UCN2 reversed skin inflammation in humanized mice. We propose the neuropeptide UCN2 as a novel skin DC-derived immunoregulatory mediator with a potential role in UVB and VitD3-dependent skin immune homeostasis.