Platelet-activating factor receptor agonists mediate xeroderma pigmentosum A photosensitivity.
To date, oxidized glycerophosphocholines (Ox-GPCs) with platelet-activating factor (PAF) activity produced non-enzymatically have not been definitively demonstrated to mediate any known disease processes. Here we provide evidence that these Ox-GPCs play a pivotal role in the photosensitivity associated with the deficiency of the DNA repair protein xeroderma pigmentosum type A (XPA). It should be noted that XPA-deficient cells are known to have decreased antioxidant defenses. These studies demonstrate that treatment of human XPA-deficient fibroblasts with the pro-oxidative stressor ultraviolet B (UVB) radiation resulted in increased reactive oxygen species and PAF receptor (PAF-R) agonistic activity in comparison with gene-corrected cells. The UVB irradiation-generated PAF-R agonists were inhibited by antioxidants. UVB irradiation of XPA-deficient (Xpa-/-) mice also resulted in increased PAF-R agonistic activity and skin inflammation in comparison with control mice. The increased UVB irradiation-mediated skin inflammation and TNF-α production in Xpa-/- mice were blocked by systemic antioxidants and by PAF-R antagonists. Structural characterization of PAF-R-stimulating activity in UVB-irradiated XPA-deficient fibroblasts using mass spectrometry revealed increased levels of sn-2 short-chain Ox-GPCs along with native PAF. These studies support a critical role for PAF-R agonistic Ox-GPCs in the pathophysiology of XPA photosensitivity.
Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Yongxue
Y
Yao
Kathleen A
KA
Harrison
Mohammed
M
Al-Hassani
Robert C
RC
Murphy
Samin
S
Rezania
Raymond L
RL
Konger
Jeffrey B
JB
Travers
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010767:Phosphorylcholine / Q000378:metabolism; D010972:Platelet Activating Factor / Q000819:agonists* / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance; D017382:Reactive Oxygen Species / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000528:radiation effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics / Q000378:metabolism*; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics / Q000378:metabolism*
D000975:Antioxidants; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; C039351:platelet activating factor receptor; D010767:Phosphorylcholine