IOX1 impedes host inflammation in imiquimod-triggered psoriasis

Abstract

Psoriasis is a chronic autoimmune disease with an unknown etiology and highly limited treatment strategies. The drugs currently used in the treatment of psoriasis are rarely recommended for long-term use owing to the serious side effects. Although different targets have been identified for controlling psoriasis, the role of epigenetic modifications as therapeutic targets is yet to be elucidated. Here, we investigated the therapeutic potential of 8-hydroxyquinoline-5-carboxylic acid (IOX1), a novel drug with a genetic target, in psoriasis. The daily topical administration of IOX1 in a mouse model of imiquimod (IMQ)-induced psoriatic inflammation reduced inflammatory reactions in the skin and lowered the PASI score. Furthermore, intraperitoneally injected IOX1 repressed the inflammatory status induced by IMQ in psoriatic mice by reducing the mRNA levels of pro-inflammatory cytokines, restoring splenocyte populations, and regulating macrophage polarization. Our findings indicate the remedial effects of IOX1 on dermatitis psoriasis and the potential of IOX1 as a therapeutic compound in psoriasis.

Keywords: Autoimmune diseases; Inflammation; Psoriasis; Splenocytes.

Figure 1

Effects of IOX1 in an IMQ-induced psoriatic mouse model. A) Experimental schedule. Calcibeta (20 mg/cm²) was topically applied on the shaved back of mice on days 1, 3, and 5. IOX1 (5 and 10 mg/kg) was administered via intraperitoneal injection on days 1, 3, and 5. B) Psoriatic changes on the dorsal skin of mice after 7 days. C) Skin tissues were collected from mice from different groups, fixed in 10% formalin, and cut into sections of 5 μm. Staining was performed using hematoxylin and eosin. Images were acquired using a bright field microscope at 20× magnification. The results of one of three representative experiments are shown. D) Cumulative Psoriasis Area Severity Index (PASI) scoring of mice based on redness, scaling, and thickness was performed with the scores ranging from 0 to 4 (0-none, 1-mild, 2-moderate, 3-severe, and 4-very severe) on the last day of the experiment. IOX1 treatment (10 mg/kg) reduced redness (erythema) (P < 0.001), scaling (desquamation) (P < 0.05), and thickness (induration) (P < 0.01). E) IOX1 reduced skin thickness (P < 0.05). Skin thickness was measured using skin calipers. Data are presented as mean ± SEM. ∗, P < 0.05; ∗∗, P < 0.01; and ∗∗∗, P < 0.001. p < 0.05 was considered statistically significant.

Figure 2

Effects of IOX1 on the spleen and the body weight of psoriatic mice. Mice were treated with IMQ, calcibeta, and IOX1 (schedule Figure 1A), following which A) the spleen sizes were measured, and B) the spleen weights reduction were recorded (P < 0.01 for IOX1 (5 mg/kg), and P < 0.001 for IOX1 (10 mg/kg)). C) The weight changes in mice were recorded daily. D) The decreased spleen and bodyweight ratio (P < 0.05 for IOX1 (5 mg/kg), and P < 0.01 for IOX1 (10 mg/kg)) were calculated. The results of one of three representative experiments are shown. Data are presented as mean ± SEM. ∗, P < 0.05; ∗∗, P < 0.01; and ∗∗∗, P < 0.001. p < 0.05 was considered statistically significant.

Figure 3

Effects of IOX1 on the splenocytes of psoriatic mice. Flow cytometry was performed to analyze the populations of splenocytes. In contrast to IMQ group, IOX1 (10 mg/kg) A) increased significantly the population of CD4+ T cells (P < 0.001), B) the population of CD8, T cells (P < 0.001). C) lowered the population of dendritic cells (P < 0.001), and D) attenuated the upregulation of M1 macrophages (P < 0.001). Representative gating FACs plots are shown on the left-hand side. On the right-hand side. Bar charts are shown. The results of one of three representative experiments are shown. Data are presented as mean ± SEM. ∗, P < 0.05; ∗∗, P < 0.01; and ∗∗∗, P < 0.001. p < 0.05 was considered statistically significant.

Figure 4

Effects of IOX1 on pro-inflammatory cytokines in the spleen. IOX1 (10 mg/kg) reduced the mRNA levels of the cytokines (A) TNF-α (P < 0.01), (B) IL-6 (P < 0.05), (C) IL-17A (P < 0.05), (D) IL-17F (P < 0.001), and (E) IL-22 (P < 0.001) in the spleen. Data are presented as mean ± SEM. ∗, P < 0.05; ∗∗, P < 0.01; and ∗∗∗, P < 0.001. p < 0.05 was considered statistically significant.