A novel RORγt inhibitor is a potential therapeutic agent for the topical treatment of psoriasis with low risk of thymic aberrations.

Background: Retinoic acid receptor-related orphan receptor gamma t (RORγt) has critical roles in the development, maintenance and function of interleukin (IL)-17-producing cells and is a highly attractive target for the treatment of IL-17-mediated autoimmune disease, particularly psoriasis. On the other hand, RORγt is also critical for controlling apoptosis during thymopoiesis, and genetic RORγt ablation or systematic RORγt inhibition cause progressive thymic aberrations leading to T cell lymphomas.

Objective: We investigated whether topical administration of our novel RORγt inhibitor, S18-000003 has therapeutic potential for psoriasis with low risk of thymic aberrations.

Potential role of IL-17-producing CD4/CD8 double negative αβ T cells in psoriatic skin inflammation in a TPA-induced STAT3C transgenic mouse model.

Background: Psoriasis is one of the most common immune-mediated chronic inflammatory skin disorders and is accompanied by erythematous scaly plaques. There is growing evidence that the IL-23/Th17 axis plays a critical role in development of the disease. It was recently shown that in addition to CD4 Th17 cells, various IL-17-producing cell subsets such as CD8 Tc17 cells, dermal γδ T cells, and innate lymphoid cells are also involved in the development of psoriatic inflammation in humans.

Mechanism of pathogenesis of imiquimod-induced skin inflammation in the mouse: a role for interferon-alpha in dendritic cell activation by imiquimod.

Topical application of imiquimod (IMQ), a Toll-like receptor (TLR)7 ligand, can induce and exacerbate psoriasis, a chronic inflammatory skin disorder. In a mouse model of IMQ-induced psoriasis-like skin inflammation, T-helper (Th)17 cells and interleukin (IL)-17/IL-22-producing γδ-T cells have been shown to play a pivotal role. However, the mechanisms of induction of the Th17 pathway and development of psoriasis-like skin inflammation by IMQ treatment remain unclear.

Involvement of Tryptase and Proteinase-Activated Receptor-2 in Spontaneous Itch-Associated Response in Mice With Atopy-like Dermatitis.

This study investigated the involvement of tryptase and proteinase-activated receptor (PAR) subtypes in spontaneous scratching, an itch-associated behavior, in NC mice. This strain of mice showed chronic atopy-like dermatitis and severe spontaneous scratching, when kept a long time in a conventional environment. The trypsin-like serine proteinase inhibitor nafamostat mesilate (1 - 10 mg/kg) dose-dependently inhibited spontaneous scratching in mice with dermatitis.

Activation of proteinase-activated receptors induces itch-associated response through histamine-dependent and -independent pathways in mice.

Proteinase-activated receptor-2 (PAR2) participates in itch, but the role of the other subtypes of this receptor remain unknown. To investigate this issue, scratching, an itch-related behavior, was observed following intradermal injections of the activating peptides of PAR1-4 in mice. Activating peptides of PAR1, PAR2, and PAR4, but not PAR3, induced scratching.

Repeated treatment with the traditional medicine Unsei-in inhibits substance P-induced itch-associated responses through downregulation of the expression of nitric oxide synthase 1 in mice.

Unsei-in inhibits substance P (SP)-induced scratching of mice after repeated administration. The involvement of cutaneous nitric oxide (NO) in the SP-induced scratching led us to investigate the effects of Unsei-in on the cutaneous NO system in mice. Seven-day oral administration of Unsei-in (300, but not 100, mg/kg daily) significantly inhibited scratching and the increase of cutaneous NO after intradermal SP injection.