Imiquimod 5% cream induced psoriasis: a case report, summary of the literature and mechanism

Patel, Utpal; Mark, Nicholas M.; Machler, Brian C; Levine, Vicki J.

doi:10.1111/j.1365-2133.2010.10124.x

Cited by 71 publications

(85 citation statements)

References 19 publications

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“…This memory feature of skin exposure to IL-17-inducing inflammatory agents is likely to enhance protection against repeat exposure to skin-penetrating bacteria or fungal pathogens. The strong ability of γδT17 cells to expand and contribute to inflammation at a distant skin site may also provide an explanation for the ability of IMQ treatment to induce flares of disease at nontreated sites in some psoriasis patients (31).…”

Section: Discussionmentioning

confidence: 99%

Inflammation induces dermal Vγ4 ⁺ γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17–driven responses

Ramírez‐Valle

Gray

Cyster

2015

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

172

193

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Gamma delta (γδ) T cells represent a major IL-17 committed T-cell population (γδT17 cells) in the mouse dermis. Following exposure to the inflammatory agent imiquimod (IMQ) the Vγ4 + subset of γδT cells produce IL-17 in the skin and expand rapidly in draining lymph nodes (LNs). Local IMQ treatment in humans is known to exacerbate psoriasis skin lesion activity at distant sites. Whether expanded γδT17 cells sensitize distant sites to inflammation has been unknown. Here we show that expanded Vγ4 + γδT17 cells egress from LNs in a fingolimod (FTY720)-sensitive manner and use C-C chemokine receptor type 2 to accumulate in inflamed skin where they augment neutrophil recruitment and inflammation. They also travel to noninflamed skin and peripheral LNs and remain in elevated numbers at these distant sites for at least 3 mo. Sensitized mice show more rapid skin inflammation and greater proliferation and IL-17 production by Vγ4 + γδT cells upon imiquimod challenge. Transfer experiments confirm that memory-like Vγ4 + γδT17 cells respond more rapidly. Memory-like Vγ4 + γδT17 cells are distinguished by greater IL-1R1 expression and more proliferation in response to IL-1β. These findings establish that local skin inflammation leads to faster and stronger secondary responses to the same stimulus through longterm and systemic changes in the composition and properties of the dermal γδT-cell population.immunological memory | γδT cells | inflammation

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Section: Discussionmentioning

confidence: 99%

Inflammation induces dermal Vγ4 ⁺ γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17–driven responses

Ramírez‐Valle

Gray

Cyster

2015

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

172

193

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“…Imiquimod is used in humans for topical treatment of genital and perianal warts caused by human papillomavirus (23), actinic keratosis, and superficial basal cell carcinoma (24,25). Clinical application of imiquimod can also induce psoriasis or exacerbate the disease in patients with a well-controlled psoriasis (26)(27)(28)(29)(30).…”

mentioning

confidence: 99%

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

Belle

Heusch

Lemaire

et al. 2012

The Journal of Immunology

256

234

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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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“…IMQ, a TLR7/8 agonist, is widely used topically in treatment of certain virus-associated and malignant skin diseases (31). It has been reported that IMQ can induce de novo and exacerbate preexisting psoriasis lesions (32). In mice, daily application of IMQ cream induces dermatitis with many features resembling psoriasis.…”

mentioning

confidence: 99%

Blockade of Phosphatidylinositol 3-Kinase (PI3K)δ or PI3Kγ Reduces IL-17 and Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis

Roller

Perino

Dapavo

et al. 2012

The Journal of Immunology

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Psoriasis is a chronic inflammatory skin disease triggered by interplay between immune mediators from both innate and adaptive immune systems and skin tissue, in which the IL-23/IL-17 axis is critical. PI3Kδ and PI3Kγ play important roles in various immune cell functions. We found that mice lacking functional PI3Kδ or PI3Kγ are largely protected from imiquimod (IMQ)-induced psoriasis-like dermatitis, correlating with reduced IL-17 levels in the lesions, serum, and the draining lymph nodes. TCRγδ T cells were the major IL-17–producing population in the draining lymph nodes and were significantly diminished in IMQ-treated PI3Kδ knockin and PI3Kγ knockout mice. We also show that PI3Kδ and PI3Kγ inhibitors reduced IFN-γ production by human TCRγδ T cells and IL-17 and IFN-γ production by PBMCs from psoriatic or healthy donors. In addition, inhibition of PI3Kγ, but not PI3Kδ, blocked chemotaxis of CCR6+IL-17–producing cells from IMQ-treated mice or healthy human donors. Taken together, these data indicate that PI3Kδ and/or PI3Kγ inhibitors should be considered for treating IL-17–driven diseases, such as psoriasis.

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Imiquimod 5% cream induced psoriasis: a case report, summary of the literature and mechanism

Cited by 71 publications

References 19 publications

Inflammation induces dermal Vγ4 ⁺ γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17–driven responses

Inflammation induces dermal Vγ4 ⁺ γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17–driven responses

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

Blockade of Phosphatidylinositol 3-Kinase (PI3K)δ or PI3Kγ Reduces IL-17 and Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis

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Imiquimod 5% cream induced psoriasis: a case report, summary of the literature and mechanism

Cited by 71 publications

References 19 publications

Inflammation induces dermal Vγ4 + γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17–driven responses

Inflammation induces dermal Vγ4 + γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17–driven responses

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

Blockade of Phosphatidylinositol 3-Kinase (PI3K)δ or PI3Kγ Reduces IL-17 and Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis

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Inflammation induces dermal Vγ4 ⁺ γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17–driven responses

Inflammation induces dermal Vγ4 ⁺ γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17–driven responses