title: Therapeutic Elimination of the Type 1 Interferon Receptor for Treating Psoriatic Skin Inflammation.
abstract: Phototherapy with UV light is a standard treatment for psoriasis, yet the mechanisms underlying the therapeutic effects are not well understood. Studies in human and mouse keratinocytes and in the skin tissues from human patients and mice showed that UV treatment triggers ubiquitination and downregulation of the type I IFN receptor chain IFNAR1, leading to suppression of IFN signaling and an ensuing decrease in the expression of inflammatory cytokines and chemokines. The severity of imiquimod-induced psoriasiform inflammation was greatly exacerbated in skin of mice deficient in IFNAR1 ubiquitination (Ifnar1(SA)). Furthermore, these mice did not benefit from UV phototherapy. Pharmacologic induction of IFNAR1 ubiquitination and degradation by an antiprotozoal agent halofuginone also relieved psoriasiform inflammation in wild-type but not in Ifnar1(SA) mice. These data identify downregulation of IFNAR1 by UV as a major mechanism of the UV therapeutic effects against the psoriatic inflammation and provide a proof of principle for future development of agents capable of inducing IFNAR1 ubiquitination and downregulation for the treatment of psoriasis.
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Gui
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gober
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Kanstantsin V
authors.initials: KV
authors.lastname: Katlinski
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Marshall
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Meena
authors.initials: M
authors.lastname: Sharma
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Victoria P
authors.initials: VP
authors.lastname: Werth
authors.affiliation: Biogen, Cambridge, Massachusetts, USA.
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.affiliation: Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Seykora
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address: syfuchs@vet.upenn.edu.
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000528:radiation effects; D006801:Humans; D007249:Inflammation / Q000473:pathology / Q000628:therapy*; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010880:Piperidines / Q000494:pharmacology*; D011565:Psoriasis / Q000473:pathology / Q000628:therapy*; D052999:Quinazolinones / Q000494:pharmacology*; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000473:pathology; D054875:Ubiquitination / Q000187:drug effects / Q000528:radiation effects; D014467:Ultraviolet Therapy / Q000379:methods*
chemical_list: D018925:Chemokines; D016207:Cytokines; D010880:Piperidines; D052999:Quinazolinones; D053633:Receptor, Interferon alpha-beta; C010176:halofuginone