Rapid improvement of psoriasis vulgaris during drug-induced agranulocytosis

Toichi, Eiko; Tachibana, Takao; Furukawa, Fukumi

doi:10.1067/mjd.2000.103264

Cited by 53 publications

(39 citation statements)

References 7 publications

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“…Several studies have highlighted the importance of neutrophils for development of psoriasis. Drug-induced agranulocytosis was reported to lead to rapid and dramatic improvement of psoriatic plaques, and psoriatic lesions quickly returned upon full recovery of neutrophil numbers in blood (37). Such findings support the notion that IL-17/CIKSmediated signaling in keratinocytes also may regulate proliferation/differentiation of these cells in an indirect manner, possibly via neutrophils.…”

Section: Discussionsupporting

confidence: 77%

IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms

Wang

Pisitkun

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

128

114

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Psoriasis is a chronic inflammatory skin disease characterized by abnormal keratinocyte proliferation and differentiation and by an influx of inflammatory cells. The mechanisms underlying psoriasis in humans and in mouse models are poorly understood, although evidence strongly points to crucial contributions of IL-17 cytokines, which signal via the obligatory adaptor CIKS/Act1. Here we identify critical roles of CIKS/Act1-mediated signaling in imiquimod-induced psoriatic inflammation, a mouse model that shares features with the human disease. We found that IL-17 cytokines/CIKS-mediated signaling into keratinocytes is essential for neutrophilic microabscess formation and contributes to hyperproliferation and markedly attenuated differentiation of keratinocytes, at least in part via direct effects. In contrast, IL-17 cytokines/CIKS-mediated signaling into nonkeratinocytes, particularly into dermal fibroblasts, promotes cellular infiltration and, importantly, leads to enhanced the accumulation of IL-17-producing γδT cells in skin, comprising a positive feed-forward mechanism. Thus, CIKS-mediated signaling is central in the development of both dermal and epidermal hallmarks of psoriasis, inducing distinct pathologies via target cell-specific effects. CIKS-mediated signaling represents a potential therapeutic target in psoriasis.

show abstract

Section: Discussionsupporting

confidence: 77%

IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms

Wang

Pisitkun

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

128

114

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“…In vitro studies focusing on the regulation of these chemokines would be required to determine whether the latter represent specific IL-22-responsive genes or depend on IL-22 and IL-17 cooperation for their expression. Nevertheless, the pathogenic role of neutrophils in psoriasis is supported by clinical observations describing disease remission during drug-induced agranulocytosis (54). Thus, our data showing that blocking IL-22 can both affect markers of keratinocyte dysregulation and of neutrophil infiltration further support the potential clinical effectiveness of IL-22 inhibitors in psoriatic patients.…”

Section: Discussionsupporting

confidence: 63%

IL-22 Is Required for Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

Belle

Heusch

Lemaire

et al. 2012

The Journal of Immunology

251

230

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Psoriasis is a common chronic autoimmune skin disease of unknown cause that involves dysregulated interplay between immune cells and keratinocytes. IL-22 is a cytokine produced by the TH1, TH17, and TH22 subsets that are functionally implicated in the psoriatic pathology. We assessed the role of IL-22 in a mouse model where psoriasiform skin inflammation is triggered by topical application of the TLR7/8 agonist imiquimod. At the macroscopic level, scaly skin lesions induced by daily applications of imiquimod in wild-type mice were almost totally absent in IL-22–deficient mice or in mice treated with a blocking anti–IL-22 Ab. At the microscopic level, IL-22–deficient mice showed a dramatic decrease in the development of pustules and a partial decrease in acanthosis. At the molecular level, the absence or inhibition of IL-22 strongly decreased the expression of chemotactic factors such as CCL3 and CXCL3 and of biomarkers such as S100A8, S100A7, and keratin 14, which reflect the antimicrobial and hyperproliferative responses of keratinocytes. IL-22 also played a major role in neutrophil infiltration after imiquimod treatment. IL-23 was required for IL-22 production, and γδ TCR lymphocytes represented the major source of IL-22 in lymph nodes from imiquimod-treated mice. However, T cells were not absolutely required for IL-22 production because imiquimod-induced IL-22 expression in the skin is still preserved in Rag2−/− mice. Taken together, our data show that IL-22 is required for psoriasis-like lesions in the mouse imiquimod model and is produced by both T cells and innate immune cells.

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“…Moreover, neutrophil chemoattractants, including CXCL1, CXCL8 (also known as IL-8), and leukotriene B 4 (LTB 4 ), are upregulated in psoriatic skin (7,8). A case report documented psoriasis remission during drug-induced agranulocytosis and its reappearance after the recovery of neutrophil numbers in the blood (9), suggesting a critical role of neutrophils in psoriatic skin inflammation. However, the detailed kinetics of neutrophil infiltration and its pathological role in psoriasis are still unknown.…”

mentioning

confidence: 99%

Interplay between CXCR2 and BLT1 Facilitates Neutrophil Infiltration and Resultant Keratinocyte Activation in a Murine Model of Imiquimod-Induced Psoriasis

Sumida

Yanagida

Kita

et al. 2014

The Journal of Immunology

128

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Psoriasis is an inflammatory skin disease with accelerated epidermal cell turnover. Neutrophil accumulation in the skin is one of the histological characteristics of psoriasis. However, the precise mechanism and role of neutrophil infiltration remain largely unknown. In this article, we show that orchestrated action of CXCR2 and leukotriene B4 receptor BLT1 plays a key role in neutrophil recruitment during the development of imiquimod (IMQ)-induced psoriatic skin lesions in mice. Depletion of neutrophils with anti–Ly-6G Ab ameliorated the disease severity, along with reduced expression of proinflammatory cytokine IL-1β in the skin. Furthermore, CXCR2 and BLT1 coordinately promote neutrophil infiltration into the skin during the early phase of IMQ-induced inflammation. In vitro, CXCR2 ligands augment leukotriene B4 production by murine neutrophils, which, in turn, amplifies chemokine-mediated neutrophil chemotaxis via BLT1 in autocrine and/or paracrine manners. In agreement with the increased IL-19 expression in IMQ-treated mouse skin, IL-1β markedly upregulated expression of acanthosis-inducing cytokine IL-19 in human keratinocytes. We propose that coordination of chemokines, lipids, and cytokines with multiple positive feedback loops might drive the pathogenesis of psoriasis and, possibly, other inflammatory diseases as well. Interference to this positive feedback or its downstream effectors could be targets of novel anti-inflammatory treatment.

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Rapid improvement of psoriasis vulgaris during drug-induced agranulocytosis

Cited by 53 publications

References 7 publications

IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms

IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms

IL-22 Is Required for Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

Interplay between CXCR2 and BLT1 Facilitates Neutrophil Infiltration and Resultant Keratinocyte Activation in a Murine Model of Imiquimod-Induced Psoriasis

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