mTORC2-PKBα/Akt1 Serine 473 Phosphorylation Axis Is Essential for Regulation of FOXP3 Stability by Chemokine CCL3 in Psoriasis

Chen, Ling; Wu, Jinjin; Pier, Eric; Zhao, Yun; Shen, Zhu

doi:10.1038/jid.2012.333

Cited by 34 publications

(25 citation statements)

References 49 publications

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“…The CCL3 , IL19 and IL20 genes have been described to be upregulated in untreated lesional psoriatic skin, [40–42] and they were downregulated 4 days after adalimumab treatment start. Finally, IL1α and IL1β were downregulated after 4 days of adalimumab treatment start.…”

Section: Discussionmentioning

confidence: 99%

Pathway Analysis of Skin from Psoriasis Patients after Adalimumab Treatment Reveals New Early Events in the Anti-Inflammatory Mechanism of Anti-TNF-α

et al. 2016

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Psoriasis is a chronic cutaneous inflammatory disease. The immunopathogenesis is a complex interplay between T cells, dendritic cells and the epidermis in which T cells and dendritic cells maintain skin inflammation. Anti-tumour necrosis factor (anti-TNF)-α agents have been approved for therapeutic use across a range of inflammatory disorders including psoriasis, but the anti-inflammatory mechanisms of anti-TNF-α in lesional psoriatic skin are not fully understood. We investigated early events in skin from psoriasis patients after treatment with anti-TNF-α antibodies by use of bioinformatics tools. We used the Human Gene 1.0 ST Array to analyse gene expression in punch biopsies taken from psoriatic patients before and also 4 and 14 days after initiation of treatment with the anti-TNF-α agent adalimumab. The gene expression was analysed by gene set enrichment analysis using the Functional Annotation Tool from DAVID Bioinformatics Resources. The most enriched pathway was visualised by the Pathview Package on Kyoto Encyclopedia of Genes and Genomes (KEGG) graphs. The analysis revealed new very early events in psoriasis after adalimumab treatment. Some of these events have been described after longer periods of anti-TNF-α treatment when clinical and histological changes appear, suggesting that effects of anti-TNF-α treatment on gene expression appear very early before clinical and histological changes. Combining microarray data on biopsies from psoriasis patients with pathway analysis allowed us to integrate in vitro findings into the identification of mechanisms that may be important in vivo. Furthermore, these results may reflect primary effect of anti-TNF-α treatment in contrast to studies of gene expression changes following clinical and histological changes, which may reflect secondary changes correlated to the healing of the skin.

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Section: Discussionmentioning

confidence: 99%

Pathway Analysis of Skin from Psoriasis Patients after Adalimumab Treatment Reveals New Early Events in the Anti-Inflammatory Mechanism of Anti-TNF-α

et al. 2016

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“…In addition, CC-chemokine ligand 3 (CCL3), which is abundant in patients with psoriasis, has been reported to induce T reg cell dysfunction and plasticity by triggering the K48-linked polyubiquitylation and degradation of FOXP3 (REF. 105). …”

Section: Post-translational Modification Of Foxp3mentioning

confidence: 99%

The regulation of immune tolerance by FOXP3

2017

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The proper restraint of the destructive potential of the immune system is essential for maintaining health. Regulatory T (Treg) cells ensure immune homeostasis through their defining ability to suppress the activation and function of other leukocytes. The expression of the transcription factor forkhead box protein P3 (FOXP3) is a well-recognized characteristic of Treg cells, and FOXP3 is centrally involved in the establishment and maintenance of the Treg cell phenotype. In this Review, we summarize how the expression and activity of FOXP3 are regulated across multiple layers by diverse factors. The therapeutic implications of these topics for cancer and autoimmunity are also discussed.

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“…The extreme inflammatory microenvironment seen during psoriasis is a setting in which Foxp3 + Tregs exhibit ineffectiveness and plasticity (213). A link between infections and psoriasis outbreaks has been proposed, and recently, Chen et al (214) explored a potential connection hinging on Treg instability. Specifically these authors found a negative correlation between Foxp3 protein levels in the CD4 + CD25 + cells of psoriasis patients and serum levels of CCL3, a chemokine and hallmark of streptococcol infection.…”

Section: Chemokinesmentioning

confidence: 99%

Treg functional stability and its responsiveness to the microenvironment

Barbi

Pardoll

Fan

2014

Immunological Reviews

196

151

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Summary Regulatory T cells (Tregs) prevent autoimmunity and tissue damage resulting from excessive or unnecessary immune activation through their suppressive function. While their importance for proper immune control is undeniable, the stability of the Treg lineage has recently become a controversial topic. Many reports have shown dramatic loss of the signature Treg transcription factor Forkhead box protein 3 (Foxp3) and Treg function under various inflammatory conditions. Other recent studies demonstrate that most Tregs are extremely resilient in their expression of Foxp3 and the retention of suppressive function. While this debate is unlikely to be settled in the immediate future, improved understanding of the considerable heterogeneity within the Foxp3+ Treg population and how Treg subsets respond to ranging environmental cues may be keys to reconciliation. In this review, we discuss the diverse mechanisms responsible for the observed stability or instability of Foxp3+ Treg identity and function. These include transcriptional and epigenetic programs, transcript targeting and posttranslational modifications that appear responsive to numerous elements of the microenvironment. These mechanisms for Treg functional modulation add to the discussion of Treg stability.

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mTORC2-PKBα/Akt1 Serine 473 Phosphorylation Axis Is Essential for Regulation of FOXP3 Stability by Chemokine CCL3 in Psoriasis

Cited by 34 publications

References 49 publications

Pathway Analysis of Skin from Psoriasis Patients after Adalimumab Treatment Reveals New Early Events in the Anti-Inflammatory Mechanism of Anti-TNF-α

Pathway Analysis of Skin from Psoriasis Patients after Adalimumab Treatment Reveals New Early Events in the Anti-Inflammatory Mechanism of Anti-TNF-α

The regulation of immune tolerance by FOXP3

Treg functional stability and its responsiveness to the microenvironment

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