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Pellino-1 promotes intrinsic activation of skin-resident IL-17A-producing T cells in psoriasis

Authors
 Sung Hee Kim  ;  Jongwook Oh  ;  Won Seok Roh  ;  Jeyun Park  ;  Kyung Bae Chung  ;  Gwang Hee Lee  ;  Youn Sook Lee  ;  Jong Hoon Kim  ;  Heung Kyu Lee  ;  Ho Lee  ;  Chang-Ook Park  ;  Do-Young Kim  ;  Min-Geol Lee  ;  Tae-Gyun Kim 
Citation
 JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol.151(5) : 1317-1328, 2023-05 
Journal Title
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
ISSN
 0091-6749 
Issue Date
2023-05
MeSH
Animals ; Dermatitis* ; Disease Models, Animal ; Humans ; Interleukin-17 ; Mice ; NF-kappa B / metabolism ; Nuclear Proteins / genetics ; Nuclear Proteins / metabolism ; Psoriasis* ; Skin ; Ubiquitin-Protein Ligases / genetics
Keywords
Interleukin-17A ; NF-κB ; Pellino-1 ; psoriasis ; single-cell RNA sequencing ; skin-resident T cells
Abstract
Background: Psoriasis is a chronically relapsing inflammatory skin disease primarily perpetuated by skin-resident IL-17-producing T (T17) cells. Pellino-1 (Peli1) belongs to a member of E3 ubiquitin ligase mediating immune receptor signaling cascades, including nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) pathway.

Objective: We explored the potential role of Peli1 in psoriatic inflammation in the context of skin-resident T17 cells.

Methods: We performed single-cell RNA sequencing of relapsing and resolved psoriatic lesions with analysis for validation data set of psoriasis. Mice with systemic and conditional depletion of Peli1 were generated to evaluate the role of Peli1 in imiquimod-induced psoriasiform dermatitis. Pharmacologic inhibition of Peli1 in human CD4+ T cells and ex vivo human skin cultures was also examined to evaluate its potential therapeutic implications.

Results: Single-cell RNA sequencing analysis revealed distinct T-cell subsets in relapsing psoriasis exhibiting highly enriched gene signatures for (1) tissue-resident T cells, (2) T17 cells, and (3) NF-κB signaling pathway including PELI1. Peli1-deficient mice were profoundly protected from psoriasiform dermatitis, with reduced IL-17A production and NF-κB activation in γδ T17 cells. Mice with conditional depletion of Peli1 treated with FTY720 revealed that Peli1 was intrinsically required for the skin-resident T17 cell immune responses. Notably, pharmacologic inhibition of Peli1 significantly ameliorated murine psoriasiform dermatitis and IL-17A production from the stimulated human CD4+ T cells and ex vivo skin explants modeling psoriasis.

Conclusion: Targeting Peli1 would be a promising therapeutic strategy for psoriasis by limiting skin-resident T17 cell immune responses.
Full Text
https://www.sciencedirect.com/science/article/pii/S0091674923000349
DOI
10.1016/j.jaci.2022.12.823
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Do Young(김도영) ORCID logo https://orcid.org/0000-0002-0194-9854
Kim, Jong Hoon(김종훈) ORCID logo https://orcid.org/0000-0002-3385-8180
Kim, Tae-Gyun(김태균) ORCID logo https://orcid.org/0000-0002-2116-4579
Park, Jeyun(박제연)
Park, Chang Ook(박창욱) ORCID logo https://orcid.org/0000-0003-3856-1201
Lee, Min Geol(이민걸) ORCID logo https://orcid.org/0000-0001-7040-5335
Chung, Kyung Bae(정경배)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/195953
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