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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-skin expresses and secretes increased levels of TSLP(A) Positive control for TSLP mRNA expression in LPS-treated (n=5) or untreated (n=5) BMDCs (** p=0.0079). (B-E) Skin samples were isolated and analyzed for TSLP gene expression in (B) full thickness ear skin (E7, n=7 and C57, n=6; ** p<0.005) and (C) epidermal sheets (E7, n=4 and C57, n=4; * p=<0.05). (D) TSLP protein present in ear skin homogenates (E7, n=11 and C57, n=11; **** p<0.0001) or (E) secreted following ear skin explant culture (E7, n=12 and C57, n=12; **** p<0.0001). (F) TSLP mRNA expression in EL4 cells +/− E7 expression (n=5, **p=0.0079). Data are pooled from 2-3 independent experiments and analyzed using a Mann-Whitney t-test. ND = Not Detected (value of 0). Bars represent median values.
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Figure 2: K14.E7-skin expresses and secretes increased levels of TSLP(A) Positive control for TSLP mRNA expression in LPS-treated (n=5) or untreated (n=5) BMDCs (** p=0.0079). (B-E) Skin samples were isolated and analyzed for TSLP gene expression in (B) full thickness ear skin (E7, n=7 and C57, n=6; ** p<0.005) and (C) epidermal sheets (E7, n=4 and C57, n=4; * p=<0.05). (D) TSLP protein present in ear skin homogenates (E7, n=11 and C57, n=11; **** p<0.0001) or (E) secreted following ear skin explant culture (E7, n=12 and C57, n=12; **** p<0.0001). (F) TSLP mRNA expression in EL4 cells +/− E7 expression (n=5, **p=0.0079). Data are pooled from 2-3 independent experiments and analyzed using a Mann-Whitney t-test. ND = Not Detected (value of 0). Bars represent median values.

Mentions: Thymic stromal lymphopoietin (TSLP) may promote atopic dermatitis through induction of Th2 cytokine-mediated inflammation11, 12, therefore we examined the expression of TSLP in E7 skin. As bone marrow dendritic cells (BMDC) have been described to express TSLP in response to LPS-stimulation23, we initially confirmed the detection of TSLP in LPS-treated BMDCs (Figure 2A), and subsequently examined TSLP in E7 skin samples. TSLP mRNA was expressed at higher levels in E7 skin and epidermis than in C57 wt mice (Figure 2B, C; p < 0.05). Similarly, TSLP protein levels were higher in E7 ear skin homogenate, and secreted at higher levels following E7 skin explant culture in vitro (Figure 2D, E; p < 0.0001). To further characterize a direct role for E7 in driving TSLP expression, we compared levels of TSLP expression in EL4 cells with EL4 cells modified to express the E7 gene. As shown in Figure 2F, E7 expression significantly increased TSLP expression (p=0.0079).


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-skin expresses and secretes increased levels of TSLP(A) Positive control for TSLP mRNA expression in LPS-treated (n=5) or untreated (n=5) BMDCs (** p=0.0079). (B-E) Skin samples were isolated and analyzed for TSLP gene expression in (B) full thickness ear skin (E7, n=7 and C57, n=6; ** p<0.005) and (C) epidermal sheets (E7, n=4 and C57, n=4; * p=<0.05). (D) TSLP protein present in ear skin homogenates (E7, n=11 and C57, n=11; **** p<0.0001) or (E) secreted following ear skin explant culture (E7, n=12 and C57, n=12; **** p<0.0001). (F) TSLP mRNA expression in EL4 cells +/− E7 expression (n=5, **p=0.0079). Data are pooled from 2-3 independent experiments and analyzed using a Mann-Whitney t-test. ND = Not Detected (value of 0). Bars represent median values.
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Figure 2: K14.E7-skin expresses and secretes increased levels of TSLP(A) Positive control for TSLP mRNA expression in LPS-treated (n=5) or untreated (n=5) BMDCs (** p=0.0079). (B-E) Skin samples were isolated and analyzed for TSLP gene expression in (B) full thickness ear skin (E7, n=7 and C57, n=6; ** p<0.005) and (C) epidermal sheets (E7, n=4 and C57, n=4; * p=<0.05). (D) TSLP protein present in ear skin homogenates (E7, n=11 and C57, n=11; **** p<0.0001) or (E) secreted following ear skin explant culture (E7, n=12 and C57, n=12; **** p<0.0001). (F) TSLP mRNA expression in EL4 cells +/− E7 expression (n=5, **p=0.0079). Data are pooled from 2-3 independent experiments and analyzed using a Mann-Whitney t-test. ND = Not Detected (value of 0). Bars represent median values.
Mentions: Thymic stromal lymphopoietin (TSLP) may promote atopic dermatitis through induction of Th2 cytokine-mediated inflammation11, 12, therefore we examined the expression of TSLP in E7 skin. As bone marrow dendritic cells (BMDC) have been described to express TSLP in response to LPS-stimulation23, we initially confirmed the detection of TSLP in LPS-treated BMDCs (Figure 2A), and subsequently examined TSLP in E7 skin samples. TSLP mRNA was expressed at higher levels in E7 skin and epidermis than in C57 wt mice (Figure 2B, C; p < 0.05). Similarly, TSLP protein levels were higher in E7 ear skin homogenate, and secreted at higher levels following E7 skin explant culture in vitro (Figure 2D, E; p < 0.0001). To further characterize a direct role for E7 in driving TSLP expression, we compared levels of TSLP expression in EL4 cells with EL4 cells modified to express the E7 gene. As shown in Figure 2F, E7 expression significantly increased TSLP expression (p=0.0079).

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