Dysregulation of Akt-FOXO1 Pathway Leads to Dysfunction of Regulatory T Cells in Patients with Psoriasis

Abstract

Psoriasis is a T lymphocyteedriven systemic inflammatory disease. Regulatory T cells (Tregs) are essential for establishing and maintaining immune tolerance. In this study, we found that patients with psoriasis and healthy controls had comparable percentages of circulating CD4 þ CD25 þ FOXP3 þ Tregs, but psoriatic Tregs had reduced suppressive function. Thereafter, mRNA arrays were performed to study the gene expression profile of psoriatic Tregs. Psoriatic Tregs expressed high levels of a T helper type 1elike transcription factor and cytokines such as T-bet and IFN-g. Furthermore, we found that FOXO1 can bind to the promoter of TBX21 to inhibit its expression, thus keeping the suppressive function of Tregs. However, an increase in protein kinase Bemediated phosphorylation of FOXO1 was observed in psoriatic Tregs, which subsequently caused FOXO1 inactivation by nuclear exclusion. In addition, incubation of healthy Tregs with psoriatic serum led to the activation of protein kinase B, nuclear exclusion of FOXO1, and the loss of FOXO1 transcription activity. The role of FOXO1 in regulating the function of Tregs was corroborated using a psoriasis-like mouse model in which Foxo1-deficient Tregs failed to protect mice from developing psoriasis. In conclusion, our findings reveal that the dysregulation of the protein kinase BeFOXO1 pathway may be a critical cause of Treg dysfunction in psoriasis.

hsa_circ_0003738 Inhibits the Suppressive Function of Tregs by Targeting miR-562/IL-17A and miR-490-5p/IFN-γ Signaling Pathway

“…Our recent studies indicated that the dysregulation of the Th1 and Th17 program in psoriatic Tregs might be a critical factor in leading to the dysfunction of Tregs, which is evidenced by increased secretion of IFN-γ and IL-17A. 17 , 18 Given the evidence that circ_0003738 exerted a positive role resulting in the dysfunctional Tregs in psoriasis, we thus hypothesized that circ_0003738 might increase the secretion of these aforementioned proinflammatory cytokines in psoriatic Tregs. Flow cytometry and quantitative real-time PCR confirmed the increased expression of Th17-related cytokine IL-17A and Th1-related cytokine IFN-γ in psoriatic Tregs compared with Tregs from normal controls ( Figures 4 A–4C).…”

“…This led us to find that PKB induced nuclear export of Foxo1, and the subsequent loss of Foxo1 transcription activity enabled the Teff escape from Treg-mediated suppression. 18 Besides, a critical role for miRNAs in Tregs has been discovered. For example, miR-155 could target suppressor of cytokine signaling 1 (SOCS1) to regulate Foxp3 expression and stability, which influenced Treg differentiation and development.…”

“…17 In addition, dysregulation of protein kinase B (PKB), which induced the nuclear exclusion of Foxo1 and decreased its transcriptional activity, represented another novel mechanism for the impaired suppressive function of Tregs in psoriasis. 18 miRNAs, an important epigenetic modification, were recently uncovered to be involved in dysfunctional Tregs in psoriasis. miR-210, which is upregulated in psoriatic Tregs, could target and inhibit the expression of Foxp3 and impair the immunosuppressive functions of Tregs.…”

Expression of miR-135b in Psoriatic Skin and Its Association with Disease Improvement

“…FOXO1 is a transcription factor that regulates metabolic homeostasis in response to oxidative stress and has a key role in the function and development of Treg cells [40,41]. Interestingly, Treg cells from psoriasis are defective in the Akt-FOXO1 signaling pathway [42]. Dysfunctional or reduced Treg cells have been described in peripheral blood and in psoriatic lesional skin in patients [43][44][45].…”

Aryl Hydrocarbon Receptor in Cutaneous Vascular Endothelial Cells Restricts Psoriasis Development by Negatively Regulating Neutrophil Recruitment

“…The pathogenesis of psoriasis, a chronic recurrent inflammatory skin disease, has been revealed to be increasingly complex in the last decade. The roles of T cells and keratinocytes have been extensively investigated in previous studies (Garzorz-Stark and Eyerich, 2019;Li et al, 2019;Qiao et al, 2019). Along with epidermal hyperplasia and inflammatory cell infiltration, prominent dermal vessel dilation is one of the histological hallmarks of psoriatic lesions.…”