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Review
. 2019 Sep 13:10:2220.
doi: 10.3389/fimmu.2019.02220. eCollection 2019.

Glucocorticoids and Glucocorticoid-Induced-Leucine-Zipper (GILZ) in Psoriasis

Affiliations
Review

Glucocorticoids and Glucocorticoid-Induced-Leucine-Zipper (GILZ) in Psoriasis

Lisa M Sevilla et al. Front Immunol. .

Abstract

Psoriasis is a prevalent chronic inflammatory human disease initiated by impaired function of immune cells and epidermal keratinocytes, resulting in increased cytokine production and hyperproliferation, leading to skin lesions. Overproduction of Th1- and Th17-cytokines including interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-23, IL-17, and IL-22, is a major driver of the disease. Glucocorticoids (GCs) represent the mainstay protocol for treating psoriasis as they modulate epidermal differentiation and are potent anti-inflammatory compounds. The development of safer GC-based therapies is a high priority due to potentially severe adverse effects associated with prolonged GC use. Specific efforts have focused on downstream anti-inflammatory effectors of GC-signaling such as GC-Induced-Leucine-Zipper (GILZ), which suppresses Th17 responses and antagonizes multiple pro-inflammatory signaling pathways involved in psoriasis, including AP-1, NF-κB, STAT3, and ROR-γt. Here we review evidence regarding defective GC signaling, GC receptor (GR) function, and GILZ in psoriasis. We discuss seemingly contradicting data on the loss- and gain-of-function of GILZ in the imiquimod-induced mouse model of psoriasis. We also present potential therapeutic strategies aimed to restore GC-related pathways.

Keywords: glucocorticoid-induced-leucine-zipper (GILZ/TSC22D3); glucocorticoids (GCs); immune cells; keratinocytes; psoriasis; signaling; skin inflammation.

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Figures

Figure 1
Figure 1
Defective cutaneous GC signaling in psoriasis. Healthy skin is able to synthesize and release GCs de novo by a hypothalamic–pituitary–adrenal axis analog. The interconversion between inactive and active GCs by the enzymes 11-beta hydroxysteroid dehydrogenases type 1 and 2 (HSD11B1/HSD11B2) provides another source of corticosteroids. When local steroidogenesis is stimulated, GC-activated GR regulates gene expression, including that of Gilz. The actions of GCs in skin limit proliferation and inflammation. In psoriatic skin, de novo synthesis of GCs is strongly decreased and the expression/activity of HSD11B1/2 is impaired; decreased GC levels have an overall negative impact on epidermal differentiation. The downregulation of GR and downstream anti-inflammatory mediators in psoriatic lesions likely aggravates disease severity, including increased keratinocyte proliferation, impaired keratinocyte differentiation, and increased inflammation.
Figure 2
Figure 2
Impact of GILZ in skin psoriatic lesions: Phenotypes of GILZ−/− and GILZ-overexpressing mice. (Left) Cell type-specific contributions to cutaneous alterations in psoriatic lesions induced by the imiquimod mouse model in WT mice. Epidermal thickening (bracket), abnormal differentiation of keratinocytes (arrowhead), and intra-epidermal neutrophil infiltrates (asterisk) are indicated. Dysregulation of both immune cells and keratinocytes leads to cytokine overproduction, resulting in immune infiltrates, epidermal hyperproliferation, and abnormal epidermal differentiation. Arrows represent communication between cell types. (Right) Summary of phenotypes in GILZ−/− (34) and GILZ-overexpressing (GILZ-Tg; 18) mice. Briefly, while untreated GILZ−/− mice had increased IL-17A and IL-22 in immune cells, both GILZ−/−, and GILZ-Tg treated mice showed increased severity of imiquimod-induced psoriatic lesions. GILZ-Tg keratinocytes had constitutively increased phosphorylation of SMAD2/3, which was further increased by imiquimod. E, epidermis; D, dermis; N, neutrophils; DC, dendritic cells; KC, keratinocytes.

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References

    1. Granner DK, Wang J-C, Yamamoto KR. Regulatory actions of glucocorticoid hormones: from organisms to mechanisms. (New York, NY: Springer, 3–31. - PubMed
    1. Kadmiel M, Cidlowski JA. Glucocorticoid receptor signaling in health and disease. Trends Pharmacol Sci. (2013) 34:518–30. 10.1016/j.tips.2013.07.003 - DOI - PMC - PubMed
    1. Taves MD, Gomez-Sanchez CE, Soma KK. Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function. Am J Physiol Metab. (2011) 301:E11–24. 10.1152/ajpendo.00100.2011 - DOI - PMC - PubMed
    1. Slominski AT, Manna PR, Tuckey RC. Cutaneous glucocorticosteroidogenesis: securing local homeostasis and the skin integrity. Exp Dermatol. (2014) 23:369–74. 10.1111/exd.12376 - DOI - PMC - PubMed
    1. Weikum ER, Knuesel MT, Ortlund EA, Yamamoto KR. Glucocorticoid receptor control of transcription: precision and plasticity via allostery. Nat Rev Mol Cell Biol. (2017) 18:159–74. 10.1038/nrm.2016.152 - DOI - PMC - PubMed

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