8-methoxypsoralen plus ultraviolet A therapy acts via inhibition of the IL-23/Th17 axis and induction of Foxp3+ regulatory T cells involving CTLA4 signaling in a psoriasis-like skin disorder.
To elucidate the molecular action of 8-methoxypsoralen plus UVA (PUVA), a standard dermatological therapy, we used K5.hTGF-beta1 transgenic mice exhibiting a skin phenotype and cytokine abnormalities with strong similarities to human psoriasis. We observed that impaired function of CD4+CD25+ regulatory T cells (Tregs) and increased cytokine levels of the IL-23/Th17 pathway were responsible for the psoriatic phenotype in this mouse model. Treatment of K5.hTGF-beta1 transgenic mice with PUVA suppressed the IL-23/Th17 pathway, Th1 milieu, as well as transcription factors STAT3 and orphan nuclear receptor RORgammat. PUVA induced the Th2 pathway and IL-10-producing CD4+CD25+Foxp3+Tregs with disease-suppressive activity that was abolished by anti-CTLA4 mAb treatment. These findings were paralleled by macroscopic and microscopic clearance of the diseased murine skin. Anti-IL-17 mAb treatment also diminished the psoriatic phenotype of the mice. This indicated that both induced Tregs involving CTLA4 signaling and inhibition of the IL-23/Th17 axis are central for the therapeutic action of PUVA.
Singh
Tej Pratap
TP
Research Unit for Photodermatology, Department of Dermatology, Medical University of Graz, Graz, Austria.
Schön
Michael P
MP
Wallbrecht
Katrin
K
Michaelis
Kai
K
Rinner
Beate
B
Mayer
Gerlinde
G
Schmidbauer
Ulrike
U
Strohmaier
Heimo
H
Wang
Xiao-Jing
XJ
Wolf
Peter
P
D000818:Animals; D015703:Antigens, CD / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D060908:CTLA-4 Antigen; D002469:Cell Separation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D006801:Humans; D007118:Immunoassay; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000528:radiation effects*; D053759:Interleukin-23 / Q000187:drug effects* / Q000528:radiation effects; D008730:Methoxsalen / Q000008:administration & dosage*; D051379:Mice; D008822:Mice, Transgenic; D017319:Photosensitizing Agents / Q000008:administration & dosage*; D010789:Phototherapy; D011565:Psoriasis / Q000276:immunology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000528:radiation effects; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology; D014466:Ultraviolet Rays
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D017319:Photosensitizing Agents; D016212:Transforming Growth Factor beta; D008730:Methoxsalen