title: Blunted epidermal L-tryptophan metabolism in vitiligo affects immune response and ROS scavenging by Fenton chemistry, part 2: Epidermal H2O2/ONOO(-)-mediated stress in vitiligo hampers indoleamine 2,3-dioxygenase and aryl hydrocarbon receptor-mediated immune response signaling.
abstract: 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.
authors.affiliation: Institute for Pigmentary Disorders, E. M. Arndt University, Greifswald, Germany. k.schallreuter@bradford.ac.uk
authors.forename: Karin U
authors.initials: KU
authors.lastname: Schallreuter
authors.forename: Mohamed A E L
authors.initials: MA
authors.lastname: Salem
authors.forename: Nick C J
authors.initials: NC
authors.lastname: Gibbons
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Maitland
authors.forename: Elke
authors.initials: E
authors.lastname: Marsch
authors.forename: Souna M A
authors.initials: SM
authors.lastname: Elwary
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Healey
mesh_terms: D003198:Computer Simulation; D004817:Epidermis / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism; D014820:Vitiligo / Q000276:immunology / Q000378:metabolism*
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018336:Receptors, Aryl Hydrocarbon; D030421:Peroxynitrous Acid; D014364:Tryptophan; D006861:Hydrogen Peroxide