Immune Regulation of TNFAIP3 in Psoriasis through Its Association with Th1 and Th17 Cell Differentiation and p38 Activation

Abstract

Background. Psoriasis is an immune-mediated chronic inflammatory skin disorder in which the dysregulation of immune cells plays an important role in its development. Tumor necrosis factor- (TNF-) α antagonists affect the immune repertoire, while TNF-α-induced protein 3 (TNFAIP3) has a protective role against the deleterious effects of inflammation and participates in immune regulation. Objective. We investigated the immune regulation of TNFAIP3 in the pathogenesis of psoriasis and determined whether it is involved in the antipsoriatic effect of TNF-α antagonists. Methods. mRNA levels were evaluated in blood from patients with moderate-to-severe psoriasis. The effects of TNF-α antagonists were examined in a mouse imiquimod- (IMQ-) induced psoriasis-like dermatitis model. In the mouse model, TNFAIP3 mRNA expression was determined using RT-PCR. Serum levels of IL-17A, IL-23, IFN-γ, TNF-α, phosphorylated ERK1/2, p38, and JNK were measured using ELISA. The proportion of Th1 and Th17 cells in mouse spleens was analyzed using flow cytometry. Results. mRNA expression levels of TNFAIP3 in the blood were significantly lower in patients with moderate and severe psoriasis (mean±SD=0.44±0.25) compared with normal subjects (mean±SD=1.00±0.82) (P<0.01). In the mouse model, IMQ downregulated TNFAIP3 expression levels, which were increased after TNF-α antagonist treatment (P<0.05). Serum levels of Th17 cytokines (IL-17A and IL-23) and Th1 cytokines (IFN-γ and TNF-α) were significantly higher in the IMQ and IMQ/rat IgG1 groups compared with the control group, and the application of TNF-α antagonists significantly decreased the levels of inflammatory cytokines (P<0.01). Notably, phosphorylated p38 levels were increased in the IMQ and IMQ/rat IgG1 groups compared with the control group but were downregulated by treatment with TNF-α antagonists (P<0.05). Th1 and Th17 cells were significantly increased in the IMQ group compared with the control group (P<0.01). Conclusion. TNFAIP3 downregulation associated with Th1 and Th17 cell differentiation and p38 activation might contribute in part to the mechanism of immune dysfunction in psoriasis. TNF-α antagonists might partly exert their effects on psoriasis via this pathway.

Staphylococcus cohnii is a potentially biotherapeutic skin commensal alleviating skin inflammation

“…ATF3 has also been shown to block type 17 immunity, thereby reducing skin inflammation in a mouse model of psoriasis (Bambouskova et al, 2018). TNFAIP3 is a strong regulator of the nuclear factor kB (NF-kB)dependent proinflammatory signaling pathway and is notably downregulated in patients with AD and psoriasis (Jiang et al, 2020;Sahlol et al, 2019). Moreover, keratinocytespecific Tnfaip3 deficiency exacerbated experimental AD and IMQ-mediated psoriasis (Devos et al, 2019).…”

“…Increased expression of these genes was confirmed by qPCR (Figure 6B). These genes have been reported to have immunomodulatory effects (Bambouskova et al, 2018;Jiang et al, 2020) and thus may contribute to the observed inhibition of dermatitis. Gene Ontology biological pathway analysis revealed that steroid-hormone-related pathways were among those most significantly upregulated by S.coh 2A1 colonization (Figure 6C).…”

Sulforaphane Ameliorates the Severity of Psoriasis and SLE by Modulating Effector Cells and Reducing Oxidative Stress

“…Increasing evidence has demonstrated that inflammatory T cells such as Th1 and Th17 cells in skin lesions play important roles in the pathogenesis of psoriasis (Kagami et al, 2010;Jiang et al, 2020, Diani et al, 2015. Therefore, we sought to evaluate whether the amelioration of skin inflammation was attributed to the decreased differentiation of inflammatory T cells after sulforaphane administration.…”

Introducing New Potential Biomarkers for Celiac Disease among the Genes Extracted from General Databases

“…TNFAIP3 inhibited the expression of different proinflammatory cytokines like IL-17. [20][21][22] Recent screening studies have shown that the prevalence of CD has doubled from 0.01%-0.05% to 1-2% over the past few decades. [23][24][25] Due to the absence of accurate diagnostic tools, 75%-90% of patients with CD remain undiagnosed.…”