Overexpression of Glucocorticoid-induced Leucine Zipper (GILZ) increases susceptibility to Imiquimod-induced psoriasis and involves cutaneous activation of TGF-β1

Carceller, Elena; Ballegeer, Marlies; Deckers, Julie; Riccardi, Carlo; Bruscoli, Stefano; Hochepied, Tino; Libert, Claude; Pérez, Paloma

doi:10.1038/srep38825

Cited by 17 publications

(23 citation statements)

References 44 publications

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“…In particular, many efforts have focused on the use of GILZ as a more specific downstream mediator of GC action, which would theoretically lack undesired side-effects [ 90 ]. However, there are apparently contradictory results regarding the role of this GC target in skin inflammation as Gilz −/− mice and transgenic mice with generalized overexpression of GILZ were more susceptible to imiquimod-induced psoriasis [ 95 , 96 ].…”

Section: Gr and Mr In Adult Skin Homeostasismentioning

confidence: 99%

Roles of the Glucocorticoid and Mineralocorticoid Receptors in Skin Pathophysiology

Sevilla

Pérez

2018

IJMS

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The nuclear hormone receptor (NR) superfamily comprises approximately 50 evolutionarily conserved proteins that play major roles in gene regulation by prototypically acting as ligand-dependent transcription factors. Besides their central role in physiology, NRs have been largely used as therapeutic drug targets in many chronic inflammatory conditions and derivatives of their specific ligands, alone or in combination, are frequently prescribed for the treatment of skin diseases. In particular, glucocorticoids (GCs) are the most commonly used compounds for treating prevalent skin diseases such as psoriasis due to their anti-proliferative and anti-inflammatory actions. However, and despite their therapeutic efficacy, the long-term use of GCs is limited because of the cutaneous adverse effects including atrophy, delayed wound healing, and increased susceptibility to stress and infections. The GC receptor (GR/NR3C1) and the mineralocorticoid receptor (MR/NR3C2) are members of the NR subclass NR3C that are highly related, both structurally and functionally. While the GR is ubiquitously expressed and is almost exclusively activated by GCs; an MR has a more restricted tissue expression pattern and can bind GCs and the mineralocorticoid aldosterone with similar high affinity. As these receptors share 95% identity in their DNA binding domains; both can recognize the same hormone response elements; theoretically resulting in transcriptional regulation of the same target genes. However, a major mechanism for specific activation of GRs and/or MRs is at the pre-receptor level by modulating the local availability of active GCs. Furthermore, the selective interactions of each receptor with spatio-temporally regulated transcription factors and co-regulators are crucial for the final transcriptional outcome. While there are abundant genome wide studies identifying GR transcriptional targets in a variety of tissue and cell types; including keratinocytes; the data for MR is more limited thus far. Our group and others have studied the role of GRs and MRs in skin development and disease by generating and characterizing mouse and cellular models with gain- and loss-of-function for each receptor. Both NRs are required for skin barrier competence during mouse development and also play a role in adult skin homeostasis. Moreover, the combined loss of epidermal GRs and MRs caused a more severe skin phenotype relative to single knock-outs (KOs) in developing skin and in acute inflammation and psoriasis, indicating that these corticosteroid receptors play cooperative roles. Understanding GR- and MR-mediated signaling in skin should contribute to deciphering their tissue-specific relative roles and ultimately help to improve GC-based therapies.

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Section: Gr and Mr In Adult Skin Homeostasismentioning

confidence: 99%

Roles of the Glucocorticoid and Mineralocorticoid Receptors in Skin Pathophysiology

Sevilla

Pérez

2018

IJMS

Self Cite

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“…Recent research has demonstrated that GILZ is lacking during chronic inflammation and the inflammation arising from trauma [17,18], and that it exerts anti-inflammatory and immunosuppressive effects in these diseases. The biological activity of a full-length GILZ fusion protein has previously been described [19][20][21][22]. Our previous studies have found that full-length GILZ suppressed ICAM-1 and MCP-1 expression by dephosphorylating NF-κB p65 in retinal endothelial cells in vitro [23] and inhibited LPSinduced retinal inflammation in rats in vivo [10].…”

Section: Discussionmentioning

confidence: 90%

Synthetic Glucocorticoid-Induced Leucine Zipper Peptide Inhibits Lipopolysaccharide-Induced Ocular Inflammation in Rats

Guo

et al. 2019

Ophthalmic Res

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To demonstrate the anti-inflammatory action of a synthetic glucocorticoid-induced leucine zipper (GILZ 98-134) peptide (GILZ-p) in a model of endotoxin-induced uveitis (EIU) in rats. Methods: The EIU model was induced in Sprague Dawley rats with an intravitreal injection of lipopolysaccharide (LPS). Synthetic GILZ-p was injected intravitreally 6 h after the LPS injection. To evaluate the anti-inflammatory effects of GILZ-p, the inflammatory response in the anterior chamber and iris of the rat eyes was evaluated with a slitlamp microscope on days 0, 1, 2, 3, and 4 after GILZ-p injection. The retinal expression of inflammatory cytokines was measured on days 0, 1, 2, 3, and 4 after GILZ-p injection. Müller cell gliosis was also detected at planned time points after GILZ-p injection. Results: Anterior segment inflammation peaked at 24 h after LPS injection in the EIU model. Compared with the controls, intravitreal GILZ-p significantly suppressed LPS-induced anterior segment inflammation in the EIU rats. The levels of retinal inflammatory factors IL-1β, TNF-α, MCP-1, and ICAM-1 were simultaneously reduced by the intravitreal GILZ-p injection. The expression of vimentin in the EIU retina was significantly reduced by GILZ-p, and the downregulated aquaporin 4 in the EIU retina was significantly restored by GILZ-p. Conclusion: The synthetic GILZ-p inhibited the inflammatory reaction in the EIU model and may have utility in the treatment of inflammatory ocular disease.

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“…Both S12 and S14 also upregulated the AP-1 transcriptional regulators FosB and ATF3 in gene arrays. These genes have previously been demonstrated to be downregulated in non-lesional psoriatic skin compared with normal skin, thus suggesting that even non-lesional skin in psoriasis patients may have disturbances in ceramide metabolism and that this disturbance may predispose skin to psoriatic inflammation 8 , 40 .…”

Section: Discussionmentioning

confidence: 99%

“…Our findings have direct relevance to human psoriasis. S100A8 is upregulated by some of the current treatments for human psoriasis, namely glucocorticoids and UVA 40 , 42 , 43 . We believe this to be a compensatory upregulation of S100A8 and related molecules in response to treatment, which may be a mechanism of resistance to anti-psoriatic therapy.…”

Section: Discussionmentioning

confidence: 99%

Evidence for biochemical barrier restoration: Topical solenopsin analogs improve inflammation and acanthosis in the KC-Tie2 mouse model of psoriasis

Arbiser

Nowak

Michaels

et al. 2017

Sci Rep

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Psoriasis is a chronic inflammatory skin disease affecting 2.5–6 million patients in the United States. The cause of psoriasis remains unknown. Previous human and animal studies suggest that patients with a susceptible genetic background and some stimulus, such as barrier disruption, leads to a coordinated signaling events involving cytokines between keratinocytes, endothelial cells, T cells, macrophages and dendritic cells. Ceramides are endogenous skin lipids essential for maintaining skin barrier function and loss of ceramides may underlie inflammatory and premalignant skin. Ceramides act as a double-edged sword, promoting normal skin homeostasis in the native state, but can be metabolized to sphingosine-1-phosphate (S1P), linked to inflammation and tumorigenesis. To overcome this difficulty, we synthesized solenopsin analogs which biochemically act as ceramides, but cannot be metabolized to S1P. We assess their in vivo bioactivity in a well-established mouse model of psoriasis, the KC-Tie2 mouse. Topical solenopsin derivatives normalized cutaneous hyperplasia in this model, decreased T cell infiltration, interleukin (IL)-22 transcription, and reversed the upregulation of calprotectin and Toll-like receptor (TLR) 4 in inflamed skin. Finally, they stimulated interleukin (IL)-12 production in skin dendritic cells. Thus suggesting barrier restoration has both a biochemical and physical component, and both are necessary for optimal barrier restoration.

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Overexpression of Glucocorticoid-induced Leucine Zipper (GILZ) increases susceptibility to Imiquimod-induced psoriasis and involves cutaneous activation of TGF-β1

Cited by 17 publications

References 44 publications

Roles of the Glucocorticoid and Mineralocorticoid Receptors in Skin Pathophysiology

Roles of the Glucocorticoid and Mineralocorticoid Receptors in Skin Pathophysiology

Synthetic Glucocorticoid-Induced Leucine Zipper Peptide Inhibits Lipopolysaccharide-Induced Ocular Inflammation in Rats

Evidence for biochemical barrier restoration: Topical solenopsin analogs improve inflammation and acanthosis in the KC-Tie2 mouse model of psoriasis

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