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

doi:10.1016/j.isci.2023.108029

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

iScience. 2023 Sep 26;26(10):108029. doi: 10.1016/j.isci.2023.108029. eCollection 2023 Oct 20.

Authors

Prudence PokWai Lui^{1

2}, Chrysanthi Ainali³, Chung-Ching Chu³, Manuela Terranova-Barberio³, Panagiotis Karagiannis³, Angela Tewari³, Niloufar Safinia⁴, Ehsan Sharif-Paghaleh⁵, Sophia Tsoka⁶, Grzegorz Woszczek⁷, Paola Di Meglio³, Giovanna Lombardi¹, Antony R Young³, Frank O Nestle³, Niwa Ali^{1

2

3}

Affiliations

¹ Peter Gorer Department of Immunobiology, School of Immunology and Microbial Science, King's College London, London, UK.
² Centre for Gene Therapy and Regenerative Medicine, School of Basic and Biomedical Sciences, King's College London, London, UK.
³ St. John's Institute of Dermatology, King's College London and NIHR Biomedical Research Centre, London, UK.
⁴ Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, UK.
⁵ Department of Imaging Chemistry & Biology, School of Biomedical Engineering & Imaging Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
⁶ Department of Informatics, Faculty of Natural, Mathematical and Engineering Sciences, King's College London, Bush House, London, UK.
⁷ Asthma UK Centre in Allergic Mechanisms of Asthma, School of Immunology and Microbial Sciences, King's College London, London, UK.

Abstract

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.

Keywords: Immunology.

Grants and funding

WT_/Wellcome Trust/United Kingdom