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Blunted epidermal L‐tryptophan metabolism in vitiligo affects immune response and ROS scavenging by Fenton chemistry, part 2: epidermal H 2 O 2 /ONOO – ‐mediated stress in vitiligo hampers indoleamine 2,3‐dioxygenase and aryl hydrocarbon receptor‐mediated immune response signaling
Author(s) -
Schallreuter Karin U.,
Salem Mohamed A. E. L.,
Gibbons Nick C. J.,
Maitland Derek J.,
Marsch Elke,
Elwary Souna M. A.,
Healey Andrew R.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-201897
Subject(s) - chemistry , vitiligo , peroxynitrite , oxidative stress , biochemistry , in vivo , immune system , epidermis (zoology) , metabolism , immunology , biology , superoxide , enzyme , microbiology and biotechnology , anatomy
Vitiligo is characterized by a mostly progressive loss of the inherited skin color. The cause of the disease is still unknown, despite accumulating in vivo and in vitro evidence of massive oxidative stress via hydrogen peroxide (H 2 O 2 ) and peroxynitrite (ONOO – ) in the skin of affected individuals. The most favored hypothesis is based on autoimmune mechanisms. Since depletion of the essential amino acid L‐tryptophan (Trp) severely affects various immune responses, we here looked at Trp metabolism and signaling in these patients. Our in vivo and in vitro data revealed total absence of epidermal Trp hydroxylase activities and the presence of H 2 O 2 /ONOO – deactivated indoleamine 2,3‐dioxygenase. Aryl hydrocarbon receptor signaling is severely impaired despite the ligand (Trp dimer) being formed, as shown by mass spectrometry. Loss of this signal is supported by the absence of downstream signals (COX‐2 and CYP1A1) as well as regulatory T‐lymphocytes and by computer modeling. In vivo Fourier transform Raman spectroscopy confirmed the presence of Trp metabolites together with H 2 O 2 supporting deprivation of the epidermal Trp pool by Fenton chemistry. Taken together, our data support a long‐expressed role for in loco redox balance and a distinct immune response. These insights could open novel treatment strategies for this disease.—Schallreuter, K. U., Salem, M. A. E. L., Gibbons, N. C. J., Maitland, D. J., Marsch, E., Elwary, S., Healey, A. R. Blunted epidermal L‐tryptophan metabolism in vitiligo affects immune response and ROS scavenging by Fenton chemistry, part 2: epidermal H 2 O 2 /ONOO – ‐mediated stress in vitiligo hampers indoleamine 2,3‐dioxygenase and aryl hydrocarbon receptor‐mediated immune response signaling. FASEB J. 26, 2471‐2485 (2012). www.fasebj.org