Tumour necrosis factor-α plays a significant role in the Aldara-induced skin inflammation in mice

Vinter, Hanne; Kragballe, Knud; Steiniche, Torben; Gaestel, Matthias; Iversen, Lars; Johansen, Claus

doi:10.1111/bjd.14320

Cited by 21 publications

(16 citation statements)

References 41 publications

(107 reference statements)

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“…In addition, previous reports showed that imiquimod‐induced psoriasis mice had heavier spleen increased in size, reflecting the systemic effect of topical imiquimod . Similar to previous reports, we also identified that imiquimod group had significant body weight loss compared with vaseline group . Moreover, IL‐10 deficient mice showed more severe and persistent body weight loss than WT mice during the whole period, which point to a more severe systemic response to imiquimod.…”

Section: Discussionsupporting

confidence: 89%

“…In contrast, the score of imiquimod-applied IL-10 deficient mice remained high, which implies higher severity and chronicity. Vinter et al [39] also reported similar fading of skin inflammation despite daily application of imiquimod in WT and their genetically modified mice when the experiments were prolonged for over a week, which is the major shortcoming of the imiquimod model; "lacking chronicity." They explained that this phenomenon could be due to induction of counter-regulatory mechanisms and reported an interesting finding; increased mRNA expression of antiinflammatory IL-10 in imiquimod-applied WT mice at day 1.…”

Section: Discussionmentioning

confidence: 91%

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Imiquimod‐applied Interleukin‐10 deficient mice better reflects severe and persistent psoriasis with systemic inflammatory state

Jin

Koh

et al. 2017

Experimental Dermatology

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Previous studies have shown that imiquimod-induced psoriasis-like skin inflammation in mice resembles phenotypic changes and cytokine profiles of human psoriasis. However, a psoriasis animal model reflecting the chronic inflammatory course and comorbidities has not yet been established. We aimed to evaluate the imiquimod-applied interleukin (IL)-10 deficient mouse model in comparison with previous models. IL-10 deficient and wild-type (WT) mice received either imiquimod or vehicle cream for 12 days and were sacrificed on day 15. For earlier time point data, either imiquimod or vehicle cream was applied for 2 days, and the mice were sacrificed on day 3. Imiquimod-applied IL-10 deficient mice showed more persistent psoriasis-like inflammation and higher severity index than did WT between day 8 and 15. Histopathologically, they demonstrated significantly thicker epidermis and larger number of CD45+, myeloperoxidase+ and IL-17+ cell counts on day 15. Quantitative reverse transcription-polymerase chain reaction with skin tissue revealed significantly higher imiquimod-induced IL-23p19 expression in imiquimod-applied IL-10 deficient mice on day 15. IL-10 deficient mice also showed significantly higher serum levels of imiquimod-induced IL-17A and tumor necrosis factor-α by enzyme-linked immunosorbent assay on day 15. Furthermore, IL-10 deficient mice showed more prominent increase of spleen weight and decrease of body weight in response to imiquimod application on day 3 and 15. In conclusion, IL-10 deficient mice model with imiquimod application may better reflect severe and persistent psoriasis with systemic inflammatory state.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 91%

Imiquimod‐applied Interleukin‐10 deficient mice better reflects severe and persistent psoriasis with systemic inflammatory state

Jin

Koh

et al. 2017

Experimental Dermatology

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“…In this model, daily application of IMQ to the skin of mice induces localized skin and systemic inflammation primarily through the activation of toll-like receptor (TLR) 7/8 (van der Fits et al, 2009). The inducible inflammatory events of this model mirror aspects of human psoriasis, including the induction of psoriasis-like histologic features, activation of proinflammatory signaling pathways central to human psoriasis, and the recruitment of similar cellular infiltrates (Chamcheu et al, 2016; Grine et al, 2015; Ha et al, 2014; van der Fits et al, 2009; Vinter et al, 2016). …”

Section: Introductionmentioning

confidence: 98%

The Snowballing Literature on Imiquimod-Induced Skin Inflammation in Mice: A Critical Appraisal

Hawkes

Guðjónsson

Ward

2017

Journal of Investigative Dermatology

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Since 2009, the imiquimod- or Aldara-induced (3M Pharmaceuticals, St. Paul, MN) model of acute skin inflammation has become the most widely used mouse model in preclinical psoriasis studies. Although this model offers researchers numerous benefits, there are important limitations and possible confounding variables to consider. The imiquimod model requires careful consideration and warrants scrutiny of the data generated by its use. In this perspective, we provide an overview of the advantages and disadvantages of this mouse model and offer suggestions for its use in psoriasis research.

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“…With great interest we read the recent publication from Vinter and colleagues describing the role of TNFα in the Aldara model 1 . Through the use of scoring skin inflammation, RT-PCR, and histology, they showed that TNFα-deficient mice showed less erythema, scaling, epidermal hyperplasia, Ki67, CD3 + T cells staining and splenomegaly.…”

Section: Dear Editormentioning

confidence: 99%

Comment on ‘Tumour necrosis factor‐α plays a significant role in the Aldara‐induced skin inflammation in mice’

2016

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* CL and RV contributed equally to this work. Dear EditorWith great interest we read the recent publication from Vinter and colleagues describing the role of TNFα in the Aldara model 1 . Through the use of scoring skin inflammation, RT-PCR, and histology, they showed that TNFα-deficient mice showed less erythema, scaling, epidermal hyperplasia, Ki67, CD3 + T cells staining and splenomegaly. The authors continued by quantifying several mediating cytokines, such as IL-17A, IL-22, IL-12p40, and IL-23p19; which were significantly reduced in TNFα-knockouts. They also quantified interferon regulatory factor (IRF) -7, which on day 1 was clearly elevated in response to Aldara. Similar dynamics and levels were observed in TNFα-knockouts. Therefore, the authors conclude that TNFα does not affect the early type I interferon response. However, we believe this statement is not sufficiently supported by their study and kindly refer the authors to our previous study with TNFR1-knockout mice, which showed a sustained type I interferon response within hours after application 2 . First, we found that IFNα levels in the skin decreased in response to repetitive Aldara treatment. In contrast, TNFR1-knockouts showed steady levels instead. Measurement of IFNα and IFNβ in wild type serum revealed a peak at 3 hours after Aldara, whereas the levels kept increasing in the absence of TNFR1. A similar trend was found in the expression levels of Cxcl10, Ifit2, and Usp18; interferon-responsive genes. We attribute these results to the TNF/TNFR1 pathway negatively regulating type I interferon production in response to Aldara.Since TNFα may act through two different receptors, TNFR1 and TNFR2, it is difficult to interpret results obtained with TNFα-knockout mice only. Yet, similar to the findings of Vinter and coworkers, TNFR1-deficient mice in our study showed reduced IL-12p40 and S100A8 levels.

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Tumour necrosis factor-α plays a significant role in the Aldara-induced skin inflammation in mice

Abstract: We were able to demonstrate significantly lower levels of inflammation in TNF-α KO mice compared with WT mice, supporting the use of this model in future studies characterizing the role of TNF-α in psoriasis.

Cited by 21 publications

References 41 publications

Imiquimod‐applied Interleukin‐10 deficient mice better reflects severe and persistent psoriasis with systemic inflammatory state

Imiquimod‐applied Interleukin‐10 deficient mice better reflects severe and persistent psoriasis with systemic inflammatory state

The Snowballing Literature on Imiquimod-Induced Skin Inflammation in Mice: A Critical Appraisal

Comment on ‘Tumour necrosis factor‐α plays a significant role in the Aldara‐induced skin inflammation in mice’

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