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

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.

SUBMITTER: Lui PP

PROVIDER: S-EPMC10583083 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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

Lui Prudence PokWai PP Ainali Chrysanthi C Chu Chung-Ching CC Terranova-Barberio Manuela M Karagiannis Panagiotis P Tewari Angela A Safinia Niloufar N Sharif-Paghaleh Ehsan E Tsoka Sophia S Woszczek Grzegorz G Di Meglio Paola P Lombardi Giovanna G Young Antony R AR Nestle Frank O FO Ali Niwa N

iScience 20230926 10

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 i ...[more]

PMID: 37860766

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Project description:Human immune cell subsets develop in immunodeficient mice following reconstitution with human CD34+ hematopoietic stem cells. These "humanized" mice are useful models to study human immunology and human-tropic infections, autoimmunity, and cancer. However, some human immune cell subsets are unable to fully develop or acquire full functional capacity due to a lack of cross-reactivity of many growth factors and cytokines between species. Conventional dendritic cells (cDCs) in mice are categorized into cDC1, which mediate T helper (Th)1 and CD8+ T cell responses, and cDC2, which mediate Th2 and Th17 responses. The likely human equivalents are CD141+ DC and CD1c+ DC subsets for mouse cDC1 and cDC2, respectively, but the extent of any interspecies differences is poorly characterized. Here, we exploit the fact that human CD141+ DC and CD1c+ DC develop in humanized mice, to further explore their equivalency in vivo. Global transcriptome analysis of CD141+ DC and CD1c+ DC isolated from humanized mice demonstrated that they closely resemble those in human blood. Activation of DC subsets in vivo, with the TLR3 ligand poly I:C, and the TLR7/8 ligand R848 revealed that a core panel of genes consistent with DC maturation status were upregulated by both subsets. R848 specifically upregulated genes associated with Th17 responses by CD1c+ DC, while poly I:C upregulated IFN-λ genes specifically by CD141+ DC. MYCL expression, known to be essential for CD8+ T cell priming by mouse DC, was specifically induced in CD141+ DC after activation. Concomitantly, CD141+ DC were superior to CD1c+ DC in their ability to prime naïve antigen-specific CD8+ T cells. Thus, CD141+ DC and CD1c+ DC share a similar activation profiles in vivo but also have induce unique signatures that support specialized roles in CD8+ T cell priming and Th17 responses, respectively. In combination, these data demonstrate that humanized mice provide an attractive and tractable model to study human DC in vitro and in vivo.

Dataset Information

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

Publications

Human skin CD141<sup>+</sup> dendritic cells regulate cutaneous immunity via the neuropeptide urocortin 2.

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