Evidence for the involvement of keratinocyte‐derived microvesicle particles in the photosensitivity associated with xeroderma pigmentosum type A deficiency
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Published:2024-01-29
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Volume:
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ISSN:0031-8655
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Container-title:Photochemistry and Photobiology
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language:en
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Short-container-title:Photochem & Photobiology
Author:
Christian Lea1ORCID,
Manjrekar Pranali1ORCID,
Henkels Karen M.1,
Rapp Christine M.1ORCID,
Annamraju Risha1,
Lohade Rushabh P.1ORCID,
Singh Shikshita1,
Carpenter M. Alexandra1ORCID,
Khan Saman1ORCID,
Kemp Michael G.12ORCID,
Chen Yanfang1ORCID,
Sahu Ravi P.1,
Travers Jeffrey B.123ORCID
Affiliation:
1. Department of Pharmacology & Toxicology Wright State University Dayton Ohio USA
2. The Dayton V.A. Medical Center Dayton Ohio USA
3. Department of Dermatology Wright State University Dayton Ohio USA
Abstract
AbstractPhotosensitivity can be due to numerous causes. The photosensitivity associated with deficiency of xeroderma pigmentosum type A (XPA) has been previously shown to be associated with excess levels of the lipid mediator platelet‐activating factor (PAF) generated by the keratinocyte. As PAF has been reported to trigger the production of subcellular microvesicle particles (MVP) due to the enzyme acid sphingomyelinase (aSMase), the goal of these studies was to discern if PAF and aSMase could serve as therapeutic targets for the XPA deficiency photosensitivity. HaCaT keratinocytes lacking XPA generated greater levels of MVP in comparison to control cells. Mice deficient in XPA also generated enhanced MVP levels in skin and in plasma in response to UV radiation. Use of a genetic strategy with mice deficient in both XPA and PAF receptors revealed that these mice generated less MVP release as well as decreased skin erythema and cytokine release compared to XPA knockout mice alone. Finally, the aSMase inhibitor imipramine blocked UV‐induced MVP release in HaCaT keratinocytes, as well as XPA knockout mice. These studies support the concept that the photosensitivity associated with XPA involves PAF‐ and aSMase‐mediated MVP release and provides a potential pharmacologic target in treating this form of photosensitivity.
Funder
National Institutes of Health
National Institute of General Medical Sciences
U.S. Department of Veterans Affairs
Subject
Physical and Theoretical Chemistry,General Medicine,Biochemistry