Skin-penetrating methotrexate alleviates imiquimod-induced psoriasiform dermatitis via decreasing IL-17-producing gamma delta T cells.
Accumulating evidence has shown that the Toll-like receptor 7 agonist imiquimod (IMQ) induces psoriasiform skin inflammation in mice and that this inflammation is dependent on the IL-23/IL-17 axis. Moreover, it has been demonstrated that the main source of IL-17 is not Th17 but is dermal gamma delta (γδ) T cells in mouse psoriasiform skin. Recent advances in the understanding of immunopathogenesis of psoriasis led to an alteration in the treatment paradigm to the use of highly efficacious biologics. However, their high cost impedes the extensive use of these agents. Thus, inexpensive and safe medications are still considered valuable. In this study, we introduce the therapeutic efficacy of a newly formulated methotrexate (MTX), a chemical conjugate of MTX with cell permeable peptide, for the treatment of psoriasis. Topically applied skin-penetrating (SP)-MTX reduced the psoriasiform skin phenomenon, epidermal thickness and infiltrating immune cells into the dermis. IL-17A-producing dermal γδ T cells in the cellular infiltrate that contribute IL-23/IL-17 axis were well abrogated by SP-MTX. Furthermore, SP-MTX had no toxic effects on liver, kidney or myeloid cells, unlike systemic administration of MTX. In conclusion, topically applied SP-MTX ameliorated psoriasiform skin inflammation in mice with the criteria of clinical phenomenon, histopathology and immunology, without inducing systemic toxic effects.
Department of Dermatology, Severance Hospital, Cutaneous Biology Research Institute, Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; Department of Dermatology, School of Medicine, Health Sciences University of Mongolia, Ulaanbaatar, Mongolia.
Dashlkhumbe
D
Byamba
Do Young
DY
Kim
Dae-Suk
DS
Kim
Tae-Gyun
TG
Kim
Hyunjoong
H
Jee
Sung Hee
SH
Kim
Tae-Yoon
TY
Park
Sang-Hwa
SH
Yang
Sang-Kyou
SK
Lee
Min-Geol
MG
Lee
D000634:Aminoquinolines / Q000009:adverse effects; D000818:Animals; D039521:CD11c Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D003872:Dermatitis / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D000077271:Imiquimod; D007249:Inflammation; D020381:Interleukin-17 / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism; D008727:Methotrexate / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000737:chemistry; D010539:Permeability; D011565:Psoriasis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D012867:Skin / Q000187:drug effects* / Q000276:immunology / Q000473:pathology
D000634:Aminoquinolines; D039521:CD11c Antigen; D016207:Cytokines; D018076:DNA, Complementary; D020381:Interleukin-17; D053759:Interleukin-23; D010455:Peptides; D000077271:Imiquimod; D008727:Methotrexate
imiquimod; methotrexate; protein transduction domain; psoriasis