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Keratinocyte-derived microvesicle particles mediate ultraviolet B radiation–induced systemic immunosuppression
Langni Liu, … , R. Michael Johnson, Jeffrey B. Travers
Langni Liu, … , R. Michael Johnson, Jeffrey B. Travers
Published April 8, 2021
Citation Information: J Clin Invest. 2021;131(10):e144963. https://doi.org/10.1172/JCI144963.
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Research Article Dermatology Immunology Article has an altmetric score of 6

Keratinocyte-derived microvesicle particles mediate ultraviolet B radiation–induced systemic immunosuppression

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Abstract

A complete carcinogen, ultraviolet B (UVB) radiation (290–320 nm), is the major cause of skin cancer. UVB-induced systemic immunosuppression that contributes to photocarcinogenesis is due to the glycerophosphocholine-derived lipid mediator platelet-activating factor (PAF). A major question in photobiology is how UVB radiation, which only absorbs appreciably in the epidermal layers of skin, can generate systemic effects. UVB exposure and PAF receptor (PAFR) activation in keratinocytes induce the release of large numbers of microvesicle particles (MVPs; extracellular vesicles ranging from 100 to 1000 nm in size). MVPs released from skin keratinocytes in vitro in response to UVB (UVB-MVPs) are dependent on the keratinocyte PAFR. Here, we used both pharmacologic and genetic approaches in cells and mice to show that both the PAFR and enzyme acid sphingomyelinase (aSMase) were necessary for UVB-MVP generation. Our discovery that the calcium-sensing receptor is a keratinocyte-selective MVP marker allowed us to determine that UVB-MVPs leaving the keratinocyte can be found systemically in mice and humans following UVB exposure. Moreover, we found that UVB-MVPs contained bioactive contents including PAFR agonists that allowed them to serve as effectors for UVB downstream effects, in particular UVB-mediated systemic immunosuppression.

Authors

Langni Liu, Azeezat A. Awoyemi, Katherine E. Fahy, Pariksha Thapa, Christina Borchers, Benita Y. Wu, Cameron L. McGlone, Benjamin Schmeusser, Zafer Sattouf, Craig A. Rohan, Amy R. Williams, Elizabeth E. Cates, Christina Knisely, Lisa E. Kelly, Ji C. Bihl, David R. Cool, Ravi P. Sahu, Jinju Wang, Yanfang Chen, Christine M. Rapp, Michael G. Kemp, R. Michael Johnson, Jeffrey B. Travers

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Figure 1

UVB-induced MVP release in HaCaT keratinocytes and human skin explant tissue.

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UVB-induced MVP release in HaCaT keratinocytes and human skin explant ti...
For the in vitro studies, (A) HaCaT keratinocytes were treated with 0.1% ethanol vehicle control, 100 nM CPAF, or 3600 J/m2 UVB, and the levels of MVPs released into the supernatants were measured at various time points. (B) HaCaT keratinocytes were treated with CPAF or UVB and an inhibitor (i) of aSMase (imipramine, 50 μM), P38 MAPK (SB 203580, 10 μM), ERK 1/2 (PD 98,059, 10 μM), NF-κB (PDTC, 10 μM), or pan-caspase (Z-VAD-FMK, 24 μM) 1 hour before CPAF or UVB treatment or immediately after UVB (imipramine) treatment. The levels of MVPs released into the supernatants were measured 4 hours later. (C) For the ex vivo studies, human skin explants were either untreated or treated with vehicle (VEH) (90% ethanol plus 10% DMSO), the aSMase inhibitor imipramine (500 μM), UVB (2500 J/m2), or imipramine or vehicle 30 minutes before or immediately following UVB irradiation. Four hours later, MVPs were quantified in skin biopsies. The data in A–C are presented as the mean ± SD of 3 (B) or 4 (A and C) independent experiments. #P < 0.05; *P < 0.05 versus control (A), vehicle (B), or sham (C), by 1-way ANOVA.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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