Human skin CD141+ dendritic cells regulate cutaneous immunity via the neuropeptide urocortin 2
Prudence PokWai Lui,
Chrysanthi Ainali,
Chung-Ching Chu,
Manuela Terranova-Barberio,
Panagiotis Karagiannis,
Angela Tewari,
Niloufar Safinia,
Ehsan Sharif-Paghaleh,
Sophia Tsoka,
Grzegorz Woszczek,
Paola Di Meglio,
Giovanna Lombardi,
Antony R. Young,
Frank O. Nestle,
Niwa Ali
Affiliations
Prudence PokWai Lui
Peter Gorer Department of Immunobiology, School of Immunology and Microbial Science, King’s College London, London, UK; Centre for Gene Therapy and Regenerative Medicine, School of Basic and Biomedical Sciences, King’s College London, London, UK
Chrysanthi Ainali
St. John’s Institute of Dermatology, King’s College London and NIHR Biomedical Research Centre, London, UK
Chung-Ching Chu
St. John’s Institute of Dermatology, King’s College London and NIHR Biomedical Research Centre, London, UK
Manuela Terranova-Barberio
St. John’s Institute of Dermatology, King’s College London and NIHR Biomedical Research Centre, London, UK
Panagiotis Karagiannis
St. John’s Institute of Dermatology, King’s College London and NIHR Biomedical Research Centre, London, UK
Angela Tewari
St. John’s Institute of Dermatology, King’s College London and NIHR Biomedical Research Centre, London, UK
Niloufar Safinia
Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, James Black Centre, King’s College London, London, UK
Ehsan Sharif-Paghaleh
Department of Imaging Chemistry & Biology, School of Biomedical Engineering & Imaging Sciences, Faculty of Life Sciences & Medicine, King’s College London, London, UK
Sophia Tsoka
Department of Informatics, Faculty of Natural, Mathematical and Engineering Sciences, King’s College London, Bush House, London, UK
Grzegorz Woszczek
Asthma UK Centre in Allergic Mechanisms of Asthma, School of Immunology and Microbial Sciences, King’s College London, London, UK
Paola Di Meglio
St. John’s Institute of Dermatology, King’s College London and NIHR Biomedical Research Centre, London, UK
Giovanna Lombardi
Peter Gorer Department of Immunobiology, School of Immunology and Microbial Science, King’s College London, London, UK
Antony R. Young
St. John’s Institute of Dermatology, King’s College London and NIHR Biomedical Research Centre, London, UK
Frank O. Nestle
St. John’s Institute of Dermatology, King’s College London and NIHR Biomedical Research Centre, London, UK
Niwa Ali
Peter Gorer Department of Immunobiology, School of Immunology and Microbial Science, King’s College London, London, UK; Centre for Gene Therapy and Regenerative Medicine, School of Basic and Biomedical Sciences, King’s College London, London, UK; St. John’s Institute of Dermatology, King’s College London and NIHR Biomedical Research Centre, London, UK; Corresponding author
Summary: 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 CD141hi VitD3 moDCs. We demonstrate that CD141+ DDCs and CD141hi 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.