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HPV16 E7 expression in skin induces TSLP secretion, type 2 ILC infiltration and atopic dermatitis-like lesions.

Bergot AS, Monnet N, Le Tran S, Mittal D, Al-Kouba J, Steptoe RJ, Grimbaldeston MA, Frazer IH, Wells JW - Immunol. Cell Biol. (2015)

Bottom Line: Most commonly occurring during early childhood, atopic dermatitis is associated with eczematous lesions and lichenification, in which the epidermis becomes hypertrophied resulting in thickening of the skin.We show that HPV16 E7 expression in the skin is associated with skin thickening, acanthosis and light spongiosis.Surprisingly, skin pathology occurred independently of T cells and mast cells.

View Article: PubMed Central - PubMed

Affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.

ABSTRACT
Atopic dermatitis is a common pruritic and inflammatory skin disorder with unknown etiology. Most commonly occurring during early childhood, atopic dermatitis is associated with eczematous lesions and lichenification, in which the epidermis becomes hypertrophied resulting in thickening of the skin. In this study, we report an atopic dermatitis-like pathophysiology results in a murine model following the expression of the high-risk human papillomavirus (HPV) 16 oncoprotein E7 in keratinocytes under the keratin 14 promoter. We show that HPV16 E7 expression in the skin is associated with skin thickening, acanthosis and light spongiosis. Locally, HPV16 E7-expressing skin secreted high levels of thymic stromal lymphopoietin (TSLP) and contained increased numbers of innate lymphoid cells (ILCs). High levels of circulating immunoglobulin E were associated with increased susceptibility to skin allergy in a model of cutaneous challenge, and to airway bronchiolar inflammation, enhanced airway goblet cell metaplasia and mucus production in a model of atopic march. Surprisingly, skin pathology occurred independently of T cells and mast cells. Thus, our findings suggest that the expression of a single HPV oncogene in the skin can drive the onset of atopic dermatitis-like pathology through the induction of TSLP and type 2 ILC infiltration.

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K14.E7 transgenic mouse skin demonstrates features of atopic dermatitisRepresentative histology of E7 (A) and C57 (B) ear skin stained with H&E (scale bar = 20μm). Hyperkeratosis (κ), acanthosis (α), spongiosis (*) are indicated. C) Ear skin thickness measured in naive age-matched E7 (n=8) and C57 (n=8) mice using a caliper micrometer (*** p=0.0002). Data are pooled from 3 independent experiments and analyzed using a Mann-Whitney t-test. Bars represent median values.
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Figure 1: K14.E7 transgenic mouse skin demonstrates features of atopic dermatitisRepresentative histology of E7 (A) and C57 (B) ear skin stained with H&E (scale bar = 20μm). Hyperkeratosis (κ), acanthosis (α), spongiosis (*) are indicated. C) Ear skin thickness measured in naive age-matched E7 (n=8) and C57 (n=8) mice using a caliper micrometer (*** p=0.0002). Data are pooled from 3 independent experiments and analyzed using a Mann-Whitney t-test. Bars represent median values.

Mentions: K14.E7 transgenic mice (E7 mice) express the HPV16 E7 oncoprotein in epidermal keratinocytes under the control of the keratin 14 promoter. Histological analysis of ear skin sections show an inflammatory skin pathology (Figure 1A) compared to C57 wild-type (wt) controls (Figure 1B), with an overall increase in skin thickness (Figure 1C) 22. Pathological features of E7 ear skin include diffuse epidermal hyperplasia with hyperkeratosis, light spongiosis within the stratum spinosum, and dermal thickening, as indicated in Figure 1A. The results show that E7 mice develop characteristic pathological features of atopic dermatitis similar to those described previously in other mouse models 16, 18.


HPV16 E7 expression in skin induces TSLP secretion, type 2 ILC infiltration and atopic dermatitis-like lesions.

Bergot AS, Monnet N, Le Tran S, Mittal D, Al-Kouba J, Steptoe RJ, Grimbaldeston MA, Frazer IH, Wells JW - Immunol. Cell Biol. (2015)

K14.E7 transgenic mouse skin demonstrates features of atopic dermatitisRepresentative histology of E7 (A) and C57 (B) ear skin stained with H&E (scale bar = 20μm). Hyperkeratosis (κ), acanthosis (α), spongiosis (*) are indicated. C) Ear skin thickness measured in naive age-matched E7 (n=8) and C57 (n=8) mice using a caliper micrometer (*** p=0.0002). Data are pooled from 3 independent experiments and analyzed using a Mann-Whitney t-test. Bars represent median values.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4496302&req=5

Figure 1: K14.E7 transgenic mouse skin demonstrates features of atopic dermatitisRepresentative histology of E7 (A) and C57 (B) ear skin stained with H&E (scale bar = 20μm). Hyperkeratosis (κ), acanthosis (α), spongiosis (*) are indicated. C) Ear skin thickness measured in naive age-matched E7 (n=8) and C57 (n=8) mice using a caliper micrometer (*** p=0.0002). Data are pooled from 3 independent experiments and analyzed using a Mann-Whitney t-test. Bars represent median values.
Mentions: K14.E7 transgenic mice (E7 mice) express the HPV16 E7 oncoprotein in epidermal keratinocytes under the control of the keratin 14 promoter. Histological analysis of ear skin sections show an inflammatory skin pathology (Figure 1A) compared to C57 wild-type (wt) controls (Figure 1B), with an overall increase in skin thickness (Figure 1C) 22. Pathological features of E7 ear skin include diffuse epidermal hyperplasia with hyperkeratosis, light spongiosis within the stratum spinosum, and dermal thickening, as indicated in Figure 1A. The results show that E7 mice develop characteristic pathological features of atopic dermatitis similar to those described previously in other mouse models 16, 18.

Bottom Line: Most commonly occurring during early childhood, atopic dermatitis is associated with eczematous lesions and lichenification, in which the epidermis becomes hypertrophied resulting in thickening of the skin.We show that HPV16 E7 expression in the skin is associated with skin thickening, acanthosis and light spongiosis.Surprisingly, skin pathology occurred independently of T cells and mast cells.

View Article: PubMed Central - PubMed

Affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.

ABSTRACT
Atopic dermatitis is a common pruritic and inflammatory skin disorder with unknown etiology. Most commonly occurring during early childhood, atopic dermatitis is associated with eczematous lesions and lichenification, in which the epidermis becomes hypertrophied resulting in thickening of the skin. In this study, we report an atopic dermatitis-like pathophysiology results in a murine model following the expression of the high-risk human papillomavirus (HPV) 16 oncoprotein E7 in keratinocytes under the keratin 14 promoter. We show that HPV16 E7 expression in the skin is associated with skin thickening, acanthosis and light spongiosis. Locally, HPV16 E7-expressing skin secreted high levels of thymic stromal lymphopoietin (TSLP) and contained increased numbers of innate lymphoid cells (ILCs). High levels of circulating immunoglobulin E were associated with increased susceptibility to skin allergy in a model of cutaneous challenge, and to airway bronchiolar inflammation, enhanced airway goblet cell metaplasia and mucus production in a model of atopic march. Surprisingly, skin pathology occurred independently of T cells and mast cells. Thus, our findings suggest that the expression of a single HPV oncogene in the skin can drive the onset of atopic dermatitis-like pathology through the induction of TSLP and type 2 ILC infiltration.

Show MeSH
Related in: MedlinePlus