IL-21 Induces an Imbalance of Th17/Treg Cells in Moderate-to-Severe Plaque Psoriasis Patients

Abstract

Background: Psoriasis is a chronic immune-mediated inflammatory skin disease, with over-activated interleukin (IL)-17-producing CD4 + T cells (Th17) and repressed regulatory T (Treg) cells. IL-21 is a Th17-related cytokine and plays an important role in the pathogenesis of psoriasis. However, the mechanism by which IL-21 affects the pathogenic progress of psoriasis remains poorly understood. Methods: IL-21 and IL-21 receptor (IL-21R) expression in normal and psoriatic lesional skin were determined by immumohistochemical staining, immunofluorescence staining, and western blotting. The levels of IL-21, IL-17A, and IL-22 in the culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA). The level of IL-10 in the culture supernatants was measured by cytometric bead array (CBA). The mRNA expression levels were assessed by quantitative polymerase chain reaction (qPCR). CD4 + T cells were isolated from the peripheral blood mononuclear cells (PBMCs) from the psoriasis patients and healthy individuals and then treated with or without IL-21 for 3 days. The proportions of Th17 and Treg cells were determined by flow cytometric analysis. Results: IL-21 and IL-21R were highly expressed in the lesional skin and peripheral blood of psoriasis patients. IL-21 promoted CD4 + T cells proliferation and Th17 cells differentiation and inhibiting Treg cells differentiation by upregulating RORγt expression and downregulating Foxp3 expression, with increased expression and secretion of IL-17A and IL-22. The proportion of Treg cells was negatively correlated with that of Th17 cells in psoriasis patients. Conclusion: Our results suggest that IL-21 may promote psoriatic inflammation by inducing imbalance in Th17 and Treg cell populations.

Immunoregulatory complement receptor-1 and leukocyte-associated Ig-like receptor-1 expression on leukocytes in Psoriasis vulgaris

“… 34 The presence of impaired Tregs in PsV patients was confirmed by Shi et al. 40 These data are in line with Arbore et al. who stated that CR-1 influenced immune modulation and prevented self-damage caused by uncontrolled inflammation, which impact the pathophysiology of chronic inflammatory diseases.…”

“…Th1 and Th17 interact with monocytes and instruct monocytes to differentiate into Th1-and Th17promoting moDCs, leading to the formation of more specialised moDC subsets. 40,41 Correlation studies in severe cases revealed a significant negative correlation of the PASI score with the percentage of T lymphocytes expressing CR-1 (Figure 2). This could be explained by T€ or€ ok et al, as they demonstrated that the engagement of surface CR-1 expressed on activated CD4þve T cells augmented Treg proliferation, which suppressed the inflammation induced by Th17 cells.…”

IL-6 Is Not Absolutely Essential for the Development of a TH17 Immune Response after an Aerosol Infection with Mycobacterium tuberculosis H37rv

“…As IL-6 mediates the differentiation of TH17 cells in a Signal Transducer and Activator of Transcription (STAT)3-dependent manner [ 46 ], particularly other STAT3-activating cytokines may compensate for IL-6 during TH17 polarization. The STAT3-inducer IL-21 [ 47 ] indeed represents a crucial initiator of TH17 development under inflammatory conditions in mice and men [ 48 , 49 , 50 , 51 ]. During experimental TB, the cytokine contributes to optimal control of Mtb [ 52 , 53 ], accompanied by enhanced expression levels of Il17a [ 52 ].…”

Targeting Myeloid-Derived Suppressor Cells Is a Novel Strategy for Anti-Psoriasis Therapy

“…IL-21 is highly expressed in skin lesions and peripheral blood of psoriasis patients, which is required for epidermal hyperplasia and Th17-cell polarization [23,24,31,50]. And it was reported that IL-21 promotes psoriatic inflammation by inducing an imbalance of Th17 and Treg cells [47]. Consistent with those results, neutralizing IL-21R by its antibody abrogates IMQ-induced epidermal thickening, MDSC migration, and Th17 infiltration ( Figure 5), indicating IL-21 may be a potential therapeutic target for psoriasis treatment.…”

“…Although the role of Treg cells in psoriasis has not been fully elucidated, studies showed that numbers of Treg cells are upregulated in psoriatic skin lesions [ 41 – 44 ] or peripheral blood [ 39 , 43 , 44 ] of psoriasis patients or murine models [ 45 ]. In addition, evidence has indicated that Foxp3 + Treg cells can converse into inflammation-associated Th17 cells under proinflammatory conditions both in psoriasis [ 18 , 46 , 47 ] and in rheumatoid arthritis (RA) [ 48 ]. And there is a positive correlation between Treg cells and Th17 cells in psoriasis [ 43 ].…”