Small Extracellular Vesicles Containing miR-381-3p from Keratinocytes Promote T Helper Type 1 and T Helper Type 17 Polarization in Psoriasis.

Abstract

T helper cells are crucial for psoriasis pathogenesis. Communication between T cells and psoriatic keratinocytes (KCs) helps drive the Th1 and Th17 response, but the underlying mechanism is not well-understood. Small extracellular vesicles (sEVs) are emerging mediators of intercellular communication. Here, we investigated the role of KC-derived sEVs in the Th1 and Th17 response in psoriasis. We isolated and characterized sEVs from KCs under normal (untreated) and psoriatic (cytokine-treated) conditions. sEVs under both conditions exhibited a cup-shaped morphology and expressed markers CD63 and CD81. sEVs from cytokine-treated KCs can be taken up by CD4+T cells, leading to the induction of Th1 and Th17 polarization. Small RNA sequencing revealed that miR-381-3p was significantly increased in sEVs from cytokine-treated KCs and in CD4+T cells from patients with psoriasis. Moreover, sEVs-containing miR-381-3p was responsible for sEVs-induced Th1 and Th17 polarization. We further found that the miR-381-3p targeted to the 3' untranslated region of E3 ubiquitin-ligase UBR5 and stabilized RORγt protein expression. It also targeted to the 3' untranslated region of FOXO1, associated with activated T-bet and RORγt transcription. Taken together, we propose that psoriatic KCs transfer miR-381-3p to CD4+T cells through sEVs, inducing Th1 and Th17 polarization and promoting psoriasis development. Our findings motivate future studies of KC-derived sEVs or their specific cargoes as therapeutic candidates for psoriasis.

• Authors: Man Jiang, Hui Fang, Erle Dang, Jieyu Zhang, Pei Qiao, Chen Yu, Angang Yang, Gang Wang
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 141 Issue 3 Pg. 563-574 (03 2021) ISSN: 1523-1747 [Electronic] United States
• PMID: 32712160 (Publication Type: Journal Article, Observational Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• 3' Untranslated Regions
• Cytokines
• FOXO1 protein, human
• Forkhead Box Protein O1
• MIRN381 microRNA, human
• MicroRNAs
• Nuclear Receptor Subfamily 1, Group F, Member 3
• RORC protein, human
• UBR5 protein, human
• Ubiquitin-Protein Ligases

Topics

• 3' Untranslated Regions (genetics)
• Adult
• Case-Control Studies
• Cell Communication (immunology)
• Cytokines (metabolism)
• Extracellular Vesicles (metabolism)
• Female
• Forkhead Box Protein O1 (genetics)
• Healthy Volunteers
• Humans
• Keratinocytes (metabolism)
• Male
• MicroRNAs (metabolism)
• Middle Aged
• Nuclear Receptor Subfamily 1, Group F, Member 3 (genetics)
• Primary Cell Culture
• Psoriasis (blood, genetics, immunology, pathology)
• Sequence Analysis, RNA
• Th1 Cells (immunology, metabolism)
• Th17 Cells (immunology, metabolism)
• Ubiquitin-Protein Ligases (genetics)
• Young Adult