Fig. 3: si3033 reduces JAK1-mediated T-cell recruitment to the skin and prevents depigmentation in a mouse model of vitiligo.
From: Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin
a Single-dose subcutaneous (S.C.) injection of si3033 at 20 mg/kg supports Jak1 silencing in tail skin for over 5 weeks (n = 5 animals, mean ± s.d.; two-sided unpaired t test, *P < 0.05, **P < 0.01, ***P < 0.001); QuantiGene 2.0 assay and presented as percentage of siNTC control. b Biodistribution of si3033 at skin local to the injection site and in systemic tissues. (n = 5 animals, mean ± s.d.). c Blood chemistry diagnostics at 24 h and 72 h post S.C. injection of 20 mg/kg si3033 (n = 8 animals, mean ± s.d. the current plotting is to support visual clarity, raw data values can be found in the supplied source data file). ALB albumin, ALP alkaline phosphatase, ALT alanine transaminase, AMY amylase, Ca2+ calcium, CRE creatinine, GLU glucose, Na+ sodium, K+ potassium, TP total protein, GLOB globulin, WBC white blood cell, LYM lymphocyte, MON monocyte, NEU neutrophil, RBC red blood cell, PLT platelet, HGB hemoglobin, HCT hematocrit, MCV mean corpuscular volume, MCH mean corpuscular hemoglobin, MCHC mean corpuscular hemoglobin concentration, RDWc red blood cell distribution width coefficient of variation, RDWs red blood cell distribution width standard deviation, MPV mean platelet volume, PCT procalcitonin, PDWc platelet distribution width coefficient of variation, PDWs platelet distribution width standard deviation. d 0.08 mg of si3033 provides Jak1 silencing in the footpad skin (right vs. left pad) for 2 weeks. Mouse Jak1 mRNA were measured over 5 weeks using the QuantiGene 2.0 assay (n = 16 animals, mean ± s.d.; two-sided paired t test, *P < 0.05, **P < 0.01, ***P < 0.001). e si3033 significantly reduces the expression of IFN-γ-inducible chemokines CXCL9 and 10 in an ex vivo skin model of IFN-γ signaling at week 2. IFN-γ signaling was induced using recombinant mouse IFN-γ in a 3-mm skin punch collected at the injection site of footpad. Mouse CXCL9 and CXCL10 were quantified in the ex vivo culture media using ELISA assays (n = 10 animals, mean ± s.d.; lines represent two-sided paired t test in the same mouse, *P < 0.05). f Schematic of a mouse model of vitiligo that mimics human skin depigmentation. g Skin infiltration of autoreactive PMEL CD8+ T cells (n = 12 animals, mean ± s.d.; two-sided paired t test, **P < 0.01). h Representative image reveals that si3033 prevents skin depigmentation in footpads. The locally injected area of left footpad exhibited less severity of depigmentation compared to right footpad treated with siNTC control compound. Source data are provided as a Source Data file.
