Induced keratinocyte hyper-proliferation in α2β1 integrin transgenic mice results in systemic immune cell activation

Teige, Ingrid; Bäcklund, Alexandra; Svensson, Lars; Kvist, Peter Helding; Petersen, Thomas K.; Kemp, K.

doi:10.1016/j.intimp.2009.10.004

Cited by 16 publications

(17 citation statements)

References 32 publications

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“…As a direct response to this, variable degrees of perturbations of the epidermis were evident causing chronic inflammation and in some instances conditions reminiscent of adult plaque psoriasis [14], [62]. Such visible cutaneous abnormalities either arose spontaneously or where induced by physical irritation (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…The inflammatory response instigated by subrabasal integrin expression has previously shown to comprise T H 1- and T H 17-related cytokines like IL-1β, IFN-γ, GM-CSF and TNF-α [62]. Importantly, the T H 1 cytokine signature has been associated with the pathogenesis of psoriasis [77].…”

Section: Discussionmentioning

confidence: 99%

“…However, it is widely accepted that environmental influences, in conjunction with genetic components, play an important role in the pathogenesis of inflammatory diseases such as psoriasis. In α2/β1 integrin double-transgenic mice, skin irritation led to a chronic condition resembling psoriasis with persistent hyperplasia, cutaneous influx of CD4 + and CD8 + T-lymphocytes and secretion of pro-inflammatory cytokines like TNF-α, IFN-γ, IL-1β and IL-6 [62]. Based on our molecular analysis of central indicators of inflammation findings, we believe that the transgenic pigs may be pre-disposed for development of an exacerbated and potentially chronic inflammation by provocation.…”

Section: Discussionmentioning

confidence: 99%

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Development of Transgenic Cloned Pig Models of Skin Inflammation by DNA Transposon-Directed Ectopic Expression of Human β1 and α2 Integrin

et al. 2012

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Integrins constitute a superfamily of transmembrane signaling receptors that play pivotal roles in cutaneous homeostasis by modulating cell growth and differentiation as well as inflammatory responses in the skin. Subrabasal expression of integrins α2 and/or β1 entails hyperproliferation and aberrant differentiation of keratinocytes and leads to dermal and epidermal influx of activated T-cells. The anatomical and physiological similarities between porcine and human skin make the pig a suitable model for human skin diseases. In efforts to generate a porcine model of cutaneous inflammation, we employed the Sleeping Beauty DNA transposon system for production of transgenic cloned Göttingen minipigs expressing human β1 or α2 integrin under the control of a promoter specific for subrabasal keratinocytes. Using pools of transgenic donor fibroblasts, cloning by somatic cell nuclear transfer was utilized to produce reconstructed embryos that were subsequently transferred to surrogate sows. The resulting pigs were all transgenic and harbored from one to six transgene integrants. Molecular analyses on skin biopsies and cultured keratinocytes showed ectopic expression of the human integrins and localization within the keratinocyte plasma membrane. Markers of perturbed skin homeostasis, including activation of the MAPK pathway, increased expression of the pro-inflammatory cytokine IL-1α, and enhanced expression of the transcription factor c-Fos, were identified in keratinocytes from β1 and α2 integrin-transgenic minipigs, suggesting the induction of a chronic inflammatory phenotype in the skin. Notably, cellular dysregulation obtained by overexpression of either β1 or α2 integrin occurred through different cellular signaling pathways. Our findings mark the creation of the first cloned pig models with molecular markers of skin inflammation. Despite the absence of an overt psoriatic phenotype, these animals may possess increased susceptibility to severe skin damage-induced inflammation and should be of great potential in studies aiming at the development and refinement of topical therapies for cutaneous inflammation including psoriasis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Development of Transgenic Cloned Pig Models of Skin Inflammation by DNA Transposon-Directed Ectopic Expression of Human β1 and α2 Integrin

et al. 2012

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“…Suprabasal integrin expression is also observed during skin wound healing, in psoriasis and in some cancers. When integrins are overexpressed in the suprabasal layers of transgenic mouse epidermis this results, in the case of b1 integrins, but not a6b4, in sporadic epidermal hyperproliferation and skin inflammation associated with elevated epidermal cytokine production (Watt 2002;Owens and Watt 2003;Teige et al 2010).…”

Section: Epidermal Hyperproliferation and Wound Healingmentioning

confidence: 99%

Cell-Extracellular Matrix Interactions in Normal and Diseased Skin

Watt

Fujiwara²

2011

Cold Spring Harbor Perspectives in Biology

320

269

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Mammalian skin comprises a multi-layered epithelium, the epidermis, and an underlying connective tissue, the dermis. The epidermal extracellular matrix is a basement membrane, whereas the dermal ECM comprises fibrillar collagens and associated proteins. There is considerable heterogeneity in ECM composition within both epidermis and dermis. The functional significance of this extends beyond cell adhesion to a range of cell autonomous and nonautonomous processes, including control of epidermal stem cell fate. In skin, cell-ECM interactions influence normal homeostasis, aging, wound healing, and disease. Disturbed integrin and ECM signaling contributes to both tumor formation and fibrosis. Strategies for manipulating cell-ECM interactions to repair skin defects and intervene in a variety of skin diseases hold promise for the future.

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“…Recent evidence indicates that the induction of integrins in differentiated epidermal keratinocytes may perturb the recruitment and/or activation of immune cells [17]. For example, in transgenic mice expressing of α2β1 integrin in the suprabasal epidermal layers a local and systemic chronic inflammatory state is established in response to wound healing [18] whereas wound-induced inflammation is typically resolved within two weeks in wild-type mice. Suprabasal expression of β1-containing integrins is known to lead to an upregulation in mitogen-activated protein kinase signaling, which is sufficient to induce skin inflammation and inflammation-dependent spontaneous epidermal tumorigenesis [19].…”

Section: Introductionmentioning

confidence: 99%

Epidermal α6β4 integrin stimulates the influx of immunosuppressive cells during skin tumor promotion

Maalouf

Theivakumar

Owens

2012

Journal of Dermatological Science

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Background Induction of α6β4 integrin in the differentiated epidermal cell layers in skin is a hallmark of human cutaneous SCC pathogenesis and stimulates chemically induced SCC formation in Invα6β4 transgenic mice, which exhibit persistent expression of α6β4 in the suprabasal epidermal layers. However, the molecular basis for the support of SCC development by suprabasal α6β4 is not fully understood. Objective We examined the relevance for suprabasal α6β4 expression in the epidermis for the recruitment of immunosuppressive leukocytes during the early stages of tumor promotion. Methods In this study, we made use of the Invα6β4 transgenic mouse model, which exhibits expression of α6β4 integrin in the suprabasal layers of the epidermis driven by the involucrin promoter. First, we examined protein lysates from Invα6β4 transgenic skin using a pro-inflammatory cytokine array panel. Next, we immunofluorescence labeling of murine skin sections was employed to immunophenotype tumor promoter-treated Invα6β4 transgenic skin. Finally, a M-CSF neutralizing antibody strategy was administered to resolve Invα6β4 transgenic skin inflammation. Results Employing the Invα6β4 transgenic mouse model, we show that suprabasal α6β4 integrin expression selectively alters the profile of secreted pro-inflammatory molecules by epidermal cells, in particular CXCL5 and M-CSF, in response to acute tumor promoter treatment. The induction of CXCL5 and M-CSF in Invα6β4 transgenic epidermis was shortly followed by an exacerbated influx of CD200R+ myeloid-derived suppressor cells (MDSCs), which co-expressed the M-CSF receptor, and FoxP3+ Treg cells compared to wild-type mice. As a result, the levels of activated CD4+ T lymphocytes were dramatically diminished in Invα6β4 transgenic compared to wild-type skin, whereas similar levels of lymphocyte activation were observed in the peripheral blood. Finally, TPA-induced CD200R+ infiltrative cells and epidermal proliferation were suppressed in Invα6β4 mice treated with M-CSF neutralizing antibodies. Conclusions We conclude that aberrant expression of α6β4 integrin in post-mitotic epidermal keratinocytes stimulates a pro-tumorigenic skin microenvironment by augmenting the influx of immunosuppressive granular cells during tumor promotion.

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Induced keratinocyte hyper-proliferation in α2β1 integrin transgenic mice results in systemic immune cell activation

Cited by 16 publications

References 32 publications

Development of Transgenic Cloned Pig Models of Skin Inflammation by DNA Transposon-Directed Ectopic Expression of Human β1 and α2 Integrin

Development of Transgenic Cloned Pig Models of Skin Inflammation by DNA Transposon-Directed Ectopic Expression of Human β1 and α2 Integrin

Cell-Extracellular Matrix Interactions in Normal and Diseased Skin

Epidermal α6β4 integrin stimulates the influx of immunosuppressive cells during skin tumor promotion

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