The expression of TAM receptors and their ligand Gas6 is downregulated in psoriasis

Szász, András; Strifler, Gerda; Vörös, Andrea; Váczi, Balázs; Tubák, Vilmos; Puskás, László G.; Belső, Nóra; Kemény, Lajos; Nagy, István

doi:10.1016/j.jdermsci.2013.04.018

Cited by 6 publications

(11 citation statements)

References 10 publications

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“…Notably, in our experimental model, the expression of all three molecules is significantly downregulated in both induced and torelant iDCs (Figure 5A–C); in addition, the expression of Tyro3 and Mer is further downregulated in tolerant iDCs (Figure 5A and C). This is in line with the observed elevated level of cytokine and chemokine gene expression; moreover these data are in accordance with the recently reported marked downregulation of TAM receptor tyrosine kinases in psoriatic epidermis [23]. …”

Section: Resultssupporting

confidence: 92%

Genome Wide Transcriptome Analysis of Dendritic Cells Identifies Genes with Altered Expression in Psoriasis

et al. 2013

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Activation of dendritic cells by different pathogens induces the secretion of proinflammatory mediators resulting in local inflammation. Importantly, innate immunity must be properly controlled, as its continuous activation leads to the development of chronic inflammatory diseases such as psoriasis. Lipopolysaccharide (LPS) or peptidoglycan (PGN) induced tolerance, a phenomenon of transient unresponsiveness of cells to repeated or prolonged stimulation, proved valuable model for the study of chronic inflammation. Thus, the aim of this study was the identification of the transcriptional diversity of primary human immature dendritic cells (iDCs) upon PGN induced tolerance. Using SAGE-Seq approach, a tag-based transcriptome sequencing method, we investigated gene expression changes of primary human iDCs upon stimulation or restimulation with Staphylococcus aureus derived PGN, a widely used TLR2 ligand. Based on the expression pattern of the altered genes, we identified non-tolerizeable and tolerizeable genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (Kegg) analysis showed marked enrichment of immune-, cell cycle- and apoptosis related genes. In parallel to the marked induction of proinflammatory mediators, negative feedback regulators of innate immunity, such as TNFAIP3, TNFAIP8, Tyro3 and Mer are markedly downregulated in tolerant cells. We also demonstrate, that the expression pattern of TNFAIP3 and TNFAIP8 is altered in both lesional, and non-lesional skin of psoriatic patients. Finally, we show that pretreatment of immature dendritic cells with anti-TNF-α inhibits the expression of IL-6 and CCL1 in tolerant iDCs and partially releases the suppression of TNFAIP8. Our findings suggest that after PGN stimulation/restimulation the host cell utilizes different mechanisms in order to maintain critical balance between inflammation and tolerance. Importantly, the transcriptome sequencing of stimulated/restimulated iDCs identified numerous genes with altered expression to date not associated with role in chronic inflammation, underlying the relevance of our in vitro model for further characterization of IFN-primed iDCs.

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Section: Resultssupporting

confidence: 92%

Genome Wide Transcriptome Analysis of Dendritic Cells Identifies Genes with Altered Expression in Psoriasis

et al. 2013

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“…Plasma GAS6 levels were lower in patients with psoriasis who with at least one CM risk factor such as hypertension, hyperlipidemia, diabetes mellitus, and cigarette smoking than patients with psoriasis who have no CM risk factors, as well as healthy controls ( Figure 2). Our findings support our hypothesis, and the results of Sz asz et al [15], an animal model of psoriasis, in which GAS6 was downregulated. Sz asz et al studied only mRNAs, not protein patterns.…”

Section: Discussionsupporting

confidence: 93%

“…Sz asz et al [15] studied expression of GAS6 in psoriasis skin lesions in mice. They found that the mRNAs of TAM receptors and GAS6 are downregulated in psoriatic epidermis, and mRNA of GAS6 was negatively correlated with the expression of proinflammatory mediators in psoriasiform skin.…”

Section: Introductionmentioning

confidence: 99%

Growth Arrest‐Specific 6 and Cardiometabolic Risk Factors in Patients with Psoriasis

Sünbül

Cagman

Gerin³

et al. 2015

Cardiovascular Therapeutics

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SUMMARYObjectives: An increased risk for cardiovascular disease with psoriasis has been reported. Growth Arrest-Specific 6 (GAS6) amplifies pro-inflammatory endothelial cell activation via TAM receptors. However, it also inhibits inflammation by multiple mechanisms including phagocytosis. The objective of this study was to investigate whether plasma GAS6 levels are associated with conventional cardiometabolic (CM) risk factors in patients with psoriasis. Methods: Forty patients diagnosed with psoriasis (22 male, mean age: 43.3 AE 13.8 years) and 40 age-/sex-matched healthy controls (22 male, mean age: 39.3 AE 8.9 years) were included in the study. CM risk factors (hypertension, hyperlipidemia, diabetes mellitus, and cigarette smoking) were identified. GAS6 levels were measured by ELISA. Results: There were no significant differences between the plasma GAS6 levels of patients with psoriasis compared to the control group (6.6 AE 2.0 ng/mL, 7.6 AE 2.8 ng/mL, respectively, P > 0.05). However, GAS6 levels of patients with psoriasis having a smoking history (n = 11) were significantly lower than both patients with psoriasis who had no smoking history (n = 29) and controls (5.5 AE 1.7 ng/mL, 6.9 AE 1.9 ng/mL, 7.6 AE 2.8 ng/mL, respectively, P < 0.05). Similarly, psoriasis patients with at least one CM risk factor showed lower GAS6 levels compared to subjects without any CM risk factor (5.7 AE 1.7 ng/mL, 7.3 AE 2.0 ng/mL, P < 0.01). There was no correlation between the GAS6 level, disease duration or PASI score (r = 0.150, À0.150, and P = 0.310, 0.398, respectively). Conclusions: This pilot study provides the first evidence in humans for an association between low plasma GAS6 levels and conventional risk factors in psoriasis. Further large scale, prospective studies are needed to confirm these results.

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“…Aberrant expression of TAM members also has been reported in autoimmune disorders. For instance, reduced expression of TAM receptors in circulating immune cells as well as low plasma concentrations of TAM ligands are evident in lupus, Behcet’s disease, rheumatoid arthritis, inflammatory bowel disease, and psoriasis patients [58,99,100,101,102,103]. Interestingly, elevated concentrations of circulating soluble TAM receptors have also been detected in patients with lupus, Sjogren’s syndrome, rheumatoid arthritis, and Behcet’s disease [95,104,105,106,107], which suggest that TAM receptor shedding could have an important role in the pathogenesis of autoimmunity.…”

Section: Tam Signaling In Autoimmunitymentioning

confidence: 99%

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

Paolino

Penninger

2016

Cancers

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The TAM receptor protein tyrosine kinases—Tyro3, Axl, and Mer—are essential regulators of immune homeostasis. Guided by their cognate ligands Growth arrest-specific gene 6 (Gas6) and Protein S (Pros1), these receptors ensure the resolution of inflammation by dampening the activation of innate cells as well as by restoring tissue function through promotion of tissue repair and clearance of apoptotic cells. Their central role as negative immune regulators is highlighted by the fact that deregulation of TAM signaling has been linked to the pathogenesis of autoimmune, inflammatory, and infectious diseases. Importantly, TAM receptors have also been associated with cancer development and progression. In a cancer setting, TAM receptors have a dual regulatory role, controlling the initiation and progression of tumor development and, at the same time, the associated anti-tumor responses of diverse immune cells. Thus, modulation of TAM receptors has emerged as a potential novel strategy for cancer treatment. In this review, we discuss our current understanding of how TAM receptors control immunity, with a particular focus on the regulation of anti-tumor responses and its implications for cancer immunotherapy.

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The expression of TAM receptors and their ligand Gas6 is downregulated in psoriasis

Cited by 6 publications

References 10 publications

Genome Wide Transcriptome Analysis of Dendritic Cells Identifies Genes with Altered Expression in Psoriasis

Genome Wide Transcriptome Analysis of Dendritic Cells Identifies Genes with Altered Expression in Psoriasis

Growth Arrest‐Specific 6 and Cardiometabolic Risk Factors in Patients with Psoriasis

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

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