Topical Diacerein Decreases Skin and Splenic CD11c+ Dendritic Cells in Psoriasis

Abstract

Psoriasis is an inflammatory skin disease characterized by increased neo-vascularization, keratinocyte hyperproliferation, a pro-inflammatory cytokine milieu and immune cell infiltration. Diacerein is an anti-inflammatory drug, modulating immune cell functions, including expression and production of cytokines, in different inflammatory conditions. Therefore, we hypothesized that topical diacerein has beneficial effects on the course of psoriasis. The current study aimed to evaluate the effect of topical diacerein on imiquimod (IMQ)-induced psoriasis in C57BL/6 mice. Topical diacerein was observed to be safe without any adverse side effects in healthy or psoriatic animals. Our results demonstrated that diacerein significantly alleviated the psoriasiform-like skin inflammation over a 7-day period. Furthermore, diacerein significantly diminished the psoriasis-associated splenomegaly, indicating a systemic effect of the drug. Remarkably, we observed significantly reduced infiltration of CD11c⁺ dendritic cells (DCs) into the skin and spleen of psoriatic mice with diacerein treatment. As CD11c⁺ DCs play a pivotal role in psoriasis pathology, we consider diacerein to be a promising novel therapeutic candidate for psoriasis.

Keywords: dendritic cell; diacerein; imiquimod; psoriasis; rhein.

Figure 1

Diacerein ameliorates clinical severity of IMQ-induced psoriasis. Clinical severity is represented by the cumulative score calculated from daily semiquantitative score points for erythema, scaling, and thickening of the dorsal skin. Psoriasis was induced by daily topical application of 62.5 mg Aldara^® (IMQ) to the dorsal skin. Following IMQ, mice were treated with 100 mg of 2.5%, 5%, or 10% diacerein or placebo or the skin was left untreated. Control mice received vehicle cream. Data represent means ± SEM. n = 3–9 per group. Three independent experiments. * p < 0.05, ** p < 0.01, **** p < 0.0001, repeated measures two-way ANOVA main effects. § p < 0.05, §§ p < 0.01, §§§ p < 0.001 vs. untreated IMQ, Tukey’s multiple comparison test.

Figure 2

Diacerein reduces IMQ-induced splenomegaly. Spleen weight in mice on day 7 (A) after receiving treatment for 6 consecutive days, and on day 4 (B) after receiving treatment for 3 consecutive days. Psoriasis was induced by daily topical application of 62.5 mg Aldara^® (IMQ) to the dorsal skin. Following IMQ, mice were treated with 100 mg of 2.5%, 5%, or 10% diacerein or placebo or the skin was left untreated. Control mice received vehicle cream. Data represent means ± SEM. n = 3–6 per group. Two independent experiments (A)., ** p < 0.01, **** p < 0.0001, two-way ANOVA main effects (D = Disease; T = Treatment; I = Interaction). Sidak’s multiple comparisons test: ^†† p < 0.01; # p < 0.05, ### p < 0.01, #### p < 0.0001 vs. respective vehicle group; § p < 0.05, §§§ p < 0.001 vs. IMQ + placebo; $ p < 0.05 vs. untreated IMQ.

Figure 3

Diacerein affects spleen immune cell populations in IMQ-induced psoriasis. Flow cytometric analysis of CD45⁺ leukocytes (A), red pulp macrophages (RPMs) (B), and CD11c⁺ lymphoid dendritic cells (DCs) (C) in spleen single cell suspensions in mice on day 4 after receiving treatment for 3 consecutive days. Psoriasis was induced by daily topical application of 80.0 mg Aldara^® (IMQ) to the dorsal skin. Following IMQ, mice were treated with 100 mg of 10% diacerein or placebo or the skin was left untreated. Control mice received vehicle cream. Data represent means ± SEM. n = 5–6 per group. #### p < 0.0001, ## p < 0.01, unpaired t-test, vehicle vs. untreated IMQ; * p < 0.05, ** p < 0.01, one-way ANOVA, IMQ groups only; Tukey’s multiple comparison test: §§ p < 0.01, vs. untreated IMQ; $ p < 0.05 vs. placebo; unpaired t-test: + p < 0.05 as indicated.

Figure 4

Diacerein affects skin immune cell populations in IMQ-induced psoriasis. Flow cytometric analysis of CD45⁺ leukocytes (A), CD11b⁺ myeloid cells (B), neutrophils (C), MHCII⁺ (D) and MHCII^- (E) monocytes and macrophages, and CD11b⁺CD11c⁺ myeloid dendritic cells (DCs) (F) in skin single cell suspensions in mice on day 4 after receiving treatment for 3 consecutive days. Psoriasis was induced by daily topical application of 80.0 mg Aldara^® (IMQ) to the dorsal skin. Following IMQ, mice were treated with 100 mg of 10% diacerein or placebo or the skin was left untreated. Control mice received vehicle cream. Data represent means ± SEM. n = 5–6 per group. ### p < 0.001, #### p < 0.0001, unpaired t-test, vehicle vs. untreated IMQ; * p < 0.05, ** p < 0.01, *** p < 0.001, one-way ANOVA, IMQ groups only; § p < 0.05, §§ p < 0.01, §§§ p < 0.001, Tukey’s multiple comparison test, vs. untreated IMQ; + p < 0.05, unpaired t-test: as indicated.