Evidence for the involvement of keratinocyte ‐derived microvesicle particles in the photosensitivity associated with xeroderma pigmentosum type A deficiency

Hypothetical model by which UVR generates PAFR agonists via ROS which then result in skin inflammation. In this model, ROS generated by UVB result in MVP release via PAFR. XPA deficiency results in increased ROS and augmented responses. This process can be blocked by antioxidants, PAFR inhibitors and aSMase inhibitors. 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 photosensitivit...

Source: Photochemistry and Photobiology - January 30, 2024 Category: Science Authors: Lea Christian, Pranali Manjrekar, Karen M. Henkels, Christine  M. Rapp, Risha Annamraju, Rushabh P. Lohade, Shikshita Singh, M. Alexandra Carpenter, Saman Khan, Michael G. Kemp, Yanfang Chen, Ravi P. Sahu, Jeffrey B. Travers Tags: RESEARCH ARTICLE Source Type: research