Contribution of the IL-17 Pathway to Psoriasis and Psoriatic Arthritis

Durham, Lucy E; Kirkham, Bruce; Taams, Leonie S.

doi:10.1007/s11926-015-0529-9

Cited by 41 publications

(30 citation statements)

References 80 publications

(78 reference statements)

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“…Additionally, a transgenic mouse overexpressing IL-17C in keratinocytes develops spontaneous skin lesions with many features of human psoriasis (14). The importance of IL-17A-mediated inflammation in psoriasis has been more recently highlighted by the clinical success of biologic drugs, including IL-17A-blocking antibodies secukinumab and ixekizumab and the IL-17RA-targeting antibody brodalumab (2, 52–55). …”

Section: Discussionmentioning

confidence: 99%

MCPIP1/Regnase-1 Restricts IL-17A– and IL-17C–Dependent Skin Inflammation

Monin

Guðjónsson

Childs

et al. 2017

The Journal of Immunology

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The IL-17-family cytokines IL-17A and IL-17C drive the pathogenesis of psoriatic skin inflammation, and anti-IL-17A Abs were recently approved to treat human psoriasis. To date, little is known about mechanisms that restrain IL-17 cytokine-mediated signaling, particularly IL-17C. Here, we show that the endoribonuclease MCPIP1 (also known as Regnase-1) is markedly upregulated in human psoriatic skin lesions. Similarly, MCPIP1 was overexpressed in the imiquimod (IMQ)-driven mouse model of cutaneous inflammation. Mice with an MCPIP1 deficiency (Zc3h12a+/−) displayed no baseline skin inflammation, but they showed exacerbated pathology following IMQ treatment. Pathology in Zc3h12a+/− mice was associated with elevated expression of IL-17A- and IL-17C-dependent genes and also increased accumulation of neutrophils in skin. However, IL-17A and IL-17C expression was unaltered, suggesting that the increased inflammation in Zc3h12a+/− mice was due to enhanced downstream IL-17R signaling. Radiation chimeras demonstrated that MCPIP1 in non-hematopoietic cells is responsible for controlling skin pathology. Moreover, Zc3h12a+/−Il17ra−/− mice given IMQ showed almost no disease. To identify which IL-17RA ligand was essential, Zc3h12a+/−Il17a−/− and Zc3h12a+/−Il17c−/− mice were given IMQ; these mice had reduced but not fully abrogated pathology, indicating that MCPIP1 inhibits both IL-17A and IL-17C signaling. Confirming this hypothesis, Zc3h12a−/− keratinocytes showed increased responsiveness to IL-17A and IL-17C stimulation. Thus, MCPIP1 is a potent negative regulator of psoriatic skin inflammation through IL-17A and IL-17C. Moreover, MCPIP1 is the first described negative regulator of IL-17C signaling.

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Section: Discussionmentioning

confidence: 99%

MCPIP1/Regnase-1 Restricts IL-17A– and IL-17C–Dependent Skin Inflammation

Monin

Guðjónsson

Childs

et al. 2017

The Journal of Immunology

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“…28,29 Both IL-17 and IL-20 play a significant role in the pathogenesis of psoriasis. 29,30 Drugs blocking IL-17 are effective in treating psoriasis, 31,32 and the pharmacokinetics of anti-IL-20 antibodies are also being tested in humans for treatment of psoriasis or rheumatoid arthritis. 33 Together, these findings may suggest a relationship between certain skin pathologies and increased IL-17 and IL-20 expression.…”

Section: Discussionmentioning

confidence: 99%

Diabetic Wounds Exhibit Decreased Ym1 and Arginase Expression with Increased Expression of IL-17 and IL-20

Finley

DeClue

Sell

et al. 2016

Advances in Wound Care

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Objective: Impaired wound healing in diabetic (DB) patients is a significant health problem; however, the roles that cytokines and innate immune cells contribute to this impaired healing are not completely understood. Approach: A mouse model was used to compare the innate immune response during DB and normal wound healing. Two 5-mm full-thickness wounds were created on the dorsal skin of BKS.Cg-m+/+Leprdb/J (DB) and C57BL/6 (wildtype) mice. Innate immune cell markers and cytokine mRNA levels were measured in wound biopsies during the first week of healing. Results: Innate immune cell influx (typified by the Gr-1 neutrophil marker and the Ym1 macrophage marker) was delayed in the DB wounds. Expression of the M2 macrophage-related genes, Ym1 and arginase 1, was significantly reduced in the DB wounds. PCR array analysis demonstrated altered cytokine expression in DB wounds. Most prominently, both interleukin (IL)-17 and IL-20 mRNA levels were significantly increased in the DB wounds. Innovation: This is the first study to identify increased levels of IL-17 and IL-20 in DB wounds. These cytokines are also elevated in the inflammatory skin disorder, psoriasis; thus, they may be potential therapeutic targets to aid in DB wound healing. Conclusion: The entire cytokine profile of DB wounds over the course of healing is not completely understood. This study suggests that the IL-17 and IL-20 families of cytokines should be further analyzed in the context of DB wound healing.Keywords: diabetes, cytokine, macrophage, wound healing INTRODUCTIONIn normal wound healing, the first cells to be recruited to the wound are the polymorphonuclear cells (PMN). These cells decontaminate the wound by phagocytosing bacteria and they release chemokines and cytokines to recruit and activate macrophages in the wound. The macrophages also phagocytose bacteria, remove damaged tissue, and produce growth factors that stimulate angiogenesis, collagen deposition, and wound closure. Notably, depletion studies have suggested important roles for both PMN and macrophages in wound healing. Depletion of PMN was shown to accelerate both normal and diabetic (DB) wound healing. 1 The consequence of macrophage depletion is dependent on the phase of healing. Selective macrophage depletion (utilizing transgenic mice expressing the diphtheria toxin receptor In addition to the phase of wound healing, the role of the macrophage may depend on the subtype of macrophage that is present in each wound. Several different phenotypes of activated macrophages have been identified, including classically activated macrophages (M1) and alternatively activated macrophages (M2) (reviewed in Refs. [3][4][5] ). The M1 macrophages kill pathogens and clean the wound by removing dying cells and debris. They can also produce proteases, which may degrade the tissue. In contrast, interleukin (IL)-4 and IL-13 activate M2 macrophages, which express the mannose receptor, L-arginase 1, dectin-1, FIZZ1, and Ym1, and decreased expression of IL-1, IL-6, and tumor necrosis factor (TNF)-a.4,...

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“…Interestingly, intradermal injection of IL-22 or IL-23 into mouse ear also elicits the development of psoriasis-like disease, indicating that other cytokines in the IL-23/IL-17 axis can initiate disease [85]. The importance of IL-17A-mediated inflammation in psoriasis has been more recently highlighted by the clinical success of biologic drugs, including IL-17A-blocking antibodies secukinumab and ixekizumab and the IL-17RA-targeting antibody brodalumab [7, 130–133]. …”

Section: Il-17 Family Cytokines In Host Protection and Inflammationmentioning

confidence: 99%

Interleukin 17 Family Cytokines: Signaling Mechanisms, Biological Activities, and Therapeutic Implications

Monin

Gaffen

2017

Cold Spring Harb Perspect Biol

239

204

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The cytokines of the IL-17 family play a central role in the control of infections, especially extracellular fungi. Conversely, if unrestrained, these inflammatory cytokines contribute to the pathology in numerous autoimmune and chronic inflammatory conditions. Recent advances have led to the approval of IL-17A-blocking biologics for the treatment of moderate to severe plaque psoriasis, but much remains to be understood about the biological functions, regulation and signaling pathways downstream of these factors. In this review, we outline the current knowledge on signal transduction and known physiological activities of IL-17 family cytokines. We will highlight in particular the current understanding of these cytokines in the context of skin manifestations of disease.

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Contribution of the IL-17 Pathway to Psoriasis and Psoriatic Arthritis

Cited by 41 publications

References 80 publications

MCPIP1/Regnase-1 Restricts IL-17A– and IL-17C–Dependent Skin Inflammation

MCPIP1/Regnase-1 Restricts IL-17A– and IL-17C–Dependent Skin Inflammation

Diabetic Wounds Exhibit Decreased Ym1 and Arginase Expression with Increased Expression of IL-17 and IL-20

Interleukin 17 Family Cytokines: Signaling Mechanisms, Biological Activities, and Therapeutic Implications

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