Abstract
Psoriasis is a chronic inflammatory skin disease characterized by accelerated tumor necrosis factor-α/interleukin (IL)-23/IL-17 axis. Patients with psoriasis manifest functional defects in CD4+CD25+ forkhead box protein 3 (Foxp3)+ regulatory T cells (Tregs), which suppress the excess immune response and mediate homeostasis. Defects in Tregs contribute to the pathogenesis of psoriasis and may attribute to enhanced inhibition and/or impaired stimulation of Tregs. IL-23 induces the conversion of Tregs into type 17 helper T (Th17) cells. IL-17A reduces transforming growth factor (TGF)-β1 production, Foxp3 expression, and suppresses Treg activity. Short-chain fatty acids (SCFAs), butyrate, propionate, and acetate are microbiota-derived fermentation products that promote Treg development and function by inducing Foxp3 expression or inducing dendritic cells or intestinal epithelial cells to produce retinoic acids or TGF-β1, respectively. The gut microbiome of patients with psoriasis revealed reduced SCFA-producing bacteria, Bacteroidetes, and Faecallibacterium, which may contribute to the defect in Tregs. Therapeutic agents currently used, viz., anti-IL-23p19 or anti-IL-17A antibodies, retinoids, vitamin D3, dimethyl fumarate, narrow-band ultraviolet B, or those under development for psoriasis, viz., signal transducer and activator of transcription 3 inhibitors, butyrate, histone deacetylase inhibitors, and probiotics/prebiotics restore the defected Tregs. Thus, restoration of Tregs is a promising therapeutic target for psoriasis.
Highlights
Psoriasis is a chronic inflammatory skin disease characterized by accelerated tumor necrosis factor-α (TNF-α)/interleukin-23 (IL-23)/IL-17 axis and hyperproliferation and aberrant differentiation of epidermal keratinocytes (Figure 1) [1,2,3]
IL-6, IL-21, and IL-23 induced the phosphorylation of STAT3 in Tregs in vitro [27]. These findings indicate that IL-6, IL-21, and IL-23 cytokines whose expressions are elevated in psoriatic lesions, may impair the suppressive function of Tregs and induce the conversion of Tregs into Th1/Th17 cells via STAT3 phosphorylation
Patients with psoriasis are associated with the impaired function of Tregs and disturbed Treg/Th17 balance, which may contribute to the development and exacerbation of this disease
Summary
Psoriasis is a chronic inflammatory skin disease characterized by accelerated tumor necrosis factor-α (TNF-α)/interleukin-23 (IL-23)/IL-17 axis and hyperproliferation and aberrant differentiation of epidermal keratinocytes (Figure 1) [1,2,3]. IL-23 induces type 17 helper T (Th17) cells to proliferate and overproduce IL-17A and IL-22, which act on keratinocytes to promote their proliferation and production of the cytokines TNF-α and IL-17C; antimicrobial peptides or chemokines CXCL1/8 and CCL20 that recruit neutrophils, lymphocytes, and monocytes. Yang et al reported that Tregs from the peripheral blood of patients with psoriasis produced IFN-γ, TNF-α, and IL-17A, together with enhanced phosphorylation of STAT3 and impaired suppressive functions [27]. Serum from patients with psoriasis induced the activation of Akt and phosphorylation and cytoplasmic translocation of FOXO1 in Tregs from healthy controls in vitro, the Akt-inducing molecules in the serum were not identified. The expression of microRNA-210 is increased in circulating CD4+ T cells from patients with psoriasis, and this increase may contribute to the reduced Foxp mRNA and protein levels in the patients’ CD4+ T cells [31]. microRNA-210 binds to the 3 -untranslated region of Foxp, and the overexpression of microRNA-210 inhibits Foxp expression in CD4+ T cells from healthy controls, whereas inhibition of microRNA-210 increases Foxp expression in CD4+ T cells from patients with psoriasis
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