Upregulation of PI3K/AKT/mTOR, FABP5 and PPARβ/δ in Human Psoriasis and Imiquimod-induced Murine Psoriasiform Dermatitis Model

Chamcheu, Jean Christopher; Mi, Chaves-Rodriquez; Vm, Adhami; Ia, Siddiqui; Gs, Wood; Bj, Longley; Mukhtar, Hasan

doi:10.2340/00015555-2359

Cited by 49 publications

(89 citation statements)

References 15 publications

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“…Recent studies using RNA microarray analysis have confirmed that the disease signature observed in the IMQ mouse model reflects the human setting, specifically with respect to genes involved in epidermal development, validating the use of this model (30). Using this model, we observed that IMQ induced an epidermal signalling pattern of the mTOR pathway that resembled the situation in human psoriasis (9), which supported previous findings (22) and advocated again for the IMQ model. Topical rapamycin treatment ameliorated the severity of erythema and scaling in the psoriasis-like condition, paired with a reduction in skin thickness and a marked reduction in neovascularization in the skin.…”

Section: Discussionsupporting

confidence: 87%

“…Histologically, IMQ treatment results in keratinocyte hyperproliferation, causing abnormal epidermis differentiation with increased angiogenesis, and high infiltration of immune cells (20,21). Studies involving the use of this mouse model have shown activation of the PI3K-mTOR cascade similar to human psoriasis (22), and blockade of PI3-K in this models improved clinical symptoms (23). These findings demonstrate the functional importance of the mTOR pathway in the pathogenesis of psoriasis, and strongly advocate further development and investigation of topical rapamycin as an anti-psoriatic strategy.…”

mentioning

confidence: 97%

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Blocking mTOR Signalling with Rapamycin Ameliorates Imiquimod-induced Psoriasis in Mice

Bürger¹,

Shirsath²,

Lang³

et al. 2017

Acta Derm Venerol

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The mTOR (mechanistic target of rapamycin) inhibitor rapamycin has long been known for its immune suppressive properties, but it has shown limited therapeutic success when given systemically to patients with psoriasis. Recent data have shown that the mTOR pathway is hyperactivated in lesional psoriatic skin, which probably contributes to the disease by interfering with maturation of keratinocytes. This study investigated the effect of topical rapamycin treatment in an imiquimod-induced psoriatic mouse model. The disease was less severe if the mice had received rapamycin treatment. Immunohistological analysis revealed that rapamycin not only prevented the activation of mTOR signalling (P-mTOR and P-S6 levels), but almost normalized the expression of epidermal differentiation markers. In addition, the influx of innate immune cells into the draining lymph nodes was partially reduced by rapamycin treatment. These data emphasize the role of mTOR signalling in the pathogenesis of psoriasis, and support the investigation of topical mTOR inhibition as a novel anti-psoriatic strategy.

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Section: Discussionsupporting

confidence: 87%

mentioning

confidence: 97%

Blocking mTOR Signalling with Rapamycin Ameliorates Imiquimod-induced Psoriasis in Mice

Bürger¹,

Shirsath²,

Lang³

et al. 2017

Acta Derm Venerol

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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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“…For example, the USS identified potential non‐classical therapeutics for various cutaneous disorders such as phosphoinositide 3‐kinase pathway (PI3K) inhibitors (sirolimus, wortmannin, quinostatin and LY‐294002) and histone deacetylase (HDAC) inhibitors (scriptaid, vorinostat and CP‐690334‐01). Pharmacological inhibition of aberrant PI3K/Akt signalling has been demonstrated to have therapeutic benefit in various human and murine models of skin inflammation . Moreover, HDAC inhibitors have shown promising effects on alleviating pro‐inflammatory responses of CD8 + T cells and Langerhans cells in contact dermatitis models as well as Th17 immune responses in psoriasis .…”

Section: Discussionmentioning

confidence: 99%

Analysis of gene expression profiles of multiple skin diseases identifies a conserved signature of disrupted homeostasis

Mills

Robinson

Sherrill

et al. 2018

Experimental Dermatology

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Triggers of skin disease pathogenesis vary, but events associated with the elicitation of a lesion share many features in common. Our objective was to examine gene expression patterns in skin disease to develop a molecular signature of disruption of cutaneous homeostasis. Gene expression data from common inflammatory skin diseases (eg psoriasis, atopic dermatitis, seborrhoeic dermatitis and acne) and a novel statistical algorithm were used to define a unifying molecular signature referred to as the "unhealthy skin signature" (USS). Using a pattern-matching algorithm, analysis of public data repositories revealed that the USS is found in diverse epithelial diseases. Studies of milder disruptions of epidermal homeostasis have also shown that these conditions converge, to varying degrees, on the USS and that the degree of convergence is related directly to the severity of homeostatic disruption. The USS contains genes that had no prior published association with skin, but that play important roles in many different disease processes, supporting the importance of the USS to homeostasis. Finally, we show through pattern matching that the USS can be used to discover new potential dermatologic therapeutics. The USS provides a new means to further interrogate epithelial homeostasis and potentially develop novel therapeutics with efficacy across a spectrum of skin conditions.

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Upregulation of PI3K/AKT/mTOR, FABP5 and PPARβ/δ in Human Psoriasis and Imiquimod-induced Murine Psoriasiform Dermatitis Model

Cited by 49 publications

References 15 publications

Blocking mTOR Signalling with Rapamycin Ameliorates Imiquimod-induced Psoriasis in Mice

Blocking mTOR Signalling with Rapamycin Ameliorates Imiquimod-induced Psoriasis in Mice

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

Analysis of gene expression profiles of multiple skin diseases identifies a conserved signature of disrupted homeostasis

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