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Epidermal barrier defects link atopic dermatitis with altered skin cancer susceptibility.

Cipolat S, Hoste E, Natsuga K, Quist SR, Watt FM - Elife (2014)

Bottom Line: Atopic dermatitis can result from loss of structural proteins in the outermost epidermal layers, leading to a defective epidermal barrier.The DMBA response was normal, but EPI-/- skin exhibited an exaggerated atopic response to TPA, characterised by abnormal epidermal differentiation, a complex immune infiltrate and elevated serum thymic stromal lymphopoietin (TSLP).The exacerbated TPA response could be normalised by blocking TSLP or the immunoreceptor NKG2D but not CD4+ T cells.

View Article: PubMed Central - PubMed

Affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom.

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Effects of TSLP and NKG2D inhibition and quantitation of cytokine levels in SCCs.(A–E) CD4+ T cells (A), mast cells (B), eosinophils (C), pustules (D), and γδ T cells (E) per mm epidermis or mm2 dermis. Data are means ± SEM from at least three mice per genotype. (F and G) Serum (F) and whole skin (G) protein levels of the cytokines indicated. Data are means ± SEM from 6 IgG and 3 α-TSLP-treated mice. (H and I) Q-PCR of mRNAs indicated in SCCs. Data are means ± SEM of 4 SCCs per genotype. (J) Serum levels of TSLP in EPI−/− mice bearing papillomas smaller than 2 mm2 or at least one papilloma larger than 2 mm2. Data are means ± SEM of at least three mice per group.DOI:http://dx.doi.org/10.7554/eLife.01888.010
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fig8: Effects of TSLP and NKG2D inhibition and quantitation of cytokine levels in SCCs.(A–E) CD4+ T cells (A), mast cells (B), eosinophils (C), pustules (D), and γδ T cells (E) per mm epidermis or mm2 dermis. Data are means ± SEM from at least three mice per genotype. (F and G) Serum (F) and whole skin (G) protein levels of the cytokines indicated. Data are means ± SEM from 6 IgG and 3 α-TSLP-treated mice. (H and I) Q-PCR of mRNAs indicated in SCCs. Data are means ± SEM of 4 SCCs per genotype. (J) Serum levels of TSLP in EPI−/− mice bearing papillomas smaller than 2 mm2 or at least one papilloma larger than 2 mm2. Data are means ± SEM of at least three mice per group.DOI:http://dx.doi.org/10.7554/eLife.01888.010

Mentions: Neutralization of TSLP completely abrogated the atopic dermatitis phenotype in TPA treated EPI−/− mice (Figure 7A). Anti-NKG2D also reduced the atopic phenotype, albeit to a lesser extent (Figures 7A and 8). TPA-induced epidermal thickening was significantly reduced in TSLP or NKG2D suppressive conditions, without any differential effect on the number of PH3+ basal layer cells (Figure 7A,C, D). TSLP treatment reduced the transit time of BrdU + cells from the basal to the outermost granular layers since although the epidermis was thinner the proportion of labelled granular cells was unaffected (Figure 7E,F). There was a slight reduction in hyperkeratosis, and parakeratosis was clearly decreased (Figure 7G,H). Targeting the Rae-1/NKG2D/TSLP axis also reduced the number of dermal CD4+CD3+ lymphocytes, mast cells, eosinophils, and epidermal pustules in EPI−/− mice (Figure 8A–D). Furthermore, under TSLP suppressive conditions the number of epidermal DETCs was increased in EPI−/− skin (Figure 8E). Macrophage numbers were unaffected by TSLP or NKG2D blockade (data not shown).10.7554/eLife.01888.010Figure 8.Effects of TSLP and NKG2D inhibition and quantitation of cytokine levels in SCCs.


Epidermal barrier defects link atopic dermatitis with altered skin cancer susceptibility.

Cipolat S, Hoste E, Natsuga K, Quist SR, Watt FM - Elife (2014)

Effects of TSLP and NKG2D inhibition and quantitation of cytokine levels in SCCs.(A–E) CD4+ T cells (A), mast cells (B), eosinophils (C), pustules (D), and γδ T cells (E) per mm epidermis or mm2 dermis. Data are means ± SEM from at least three mice per genotype. (F and G) Serum (F) and whole skin (G) protein levels of the cytokines indicated. Data are means ± SEM from 6 IgG and 3 α-TSLP-treated mice. (H and I) Q-PCR of mRNAs indicated in SCCs. Data are means ± SEM of 4 SCCs per genotype. (J) Serum levels of TSLP in EPI−/− mice bearing papillomas smaller than 2 mm2 or at least one papilloma larger than 2 mm2. Data are means ± SEM of at least three mice per group.DOI:http://dx.doi.org/10.7554/eLife.01888.010
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4007207&req=5

fig8: Effects of TSLP and NKG2D inhibition and quantitation of cytokine levels in SCCs.(A–E) CD4+ T cells (A), mast cells (B), eosinophils (C), pustules (D), and γδ T cells (E) per mm epidermis or mm2 dermis. Data are means ± SEM from at least three mice per genotype. (F and G) Serum (F) and whole skin (G) protein levels of the cytokines indicated. Data are means ± SEM from 6 IgG and 3 α-TSLP-treated mice. (H and I) Q-PCR of mRNAs indicated in SCCs. Data are means ± SEM of 4 SCCs per genotype. (J) Serum levels of TSLP in EPI−/− mice bearing papillomas smaller than 2 mm2 or at least one papilloma larger than 2 mm2. Data are means ± SEM of at least three mice per group.DOI:http://dx.doi.org/10.7554/eLife.01888.010
Mentions: Neutralization of TSLP completely abrogated the atopic dermatitis phenotype in TPA treated EPI−/− mice (Figure 7A). Anti-NKG2D also reduced the atopic phenotype, albeit to a lesser extent (Figures 7A and 8). TPA-induced epidermal thickening was significantly reduced in TSLP or NKG2D suppressive conditions, without any differential effect on the number of PH3+ basal layer cells (Figure 7A,C, D). TSLP treatment reduced the transit time of BrdU + cells from the basal to the outermost granular layers since although the epidermis was thinner the proportion of labelled granular cells was unaffected (Figure 7E,F). There was a slight reduction in hyperkeratosis, and parakeratosis was clearly decreased (Figure 7G,H). Targeting the Rae-1/NKG2D/TSLP axis also reduced the number of dermal CD4+CD3+ lymphocytes, mast cells, eosinophils, and epidermal pustules in EPI−/− mice (Figure 8A–D). Furthermore, under TSLP suppressive conditions the number of epidermal DETCs was increased in EPI−/− skin (Figure 8E). Macrophage numbers were unaffected by TSLP or NKG2D blockade (data not shown).10.7554/eLife.01888.010Figure 8.Effects of TSLP and NKG2D inhibition and quantitation of cytokine levels in SCCs.

Bottom Line: Atopic dermatitis can result from loss of structural proteins in the outermost epidermal layers, leading to a defective epidermal barrier.The DMBA response was normal, but EPI-/- skin exhibited an exaggerated atopic response to TPA, characterised by abnormal epidermal differentiation, a complex immune infiltrate and elevated serum thymic stromal lymphopoietin (TSLP).The exacerbated TPA response could be normalised by blocking TSLP or the immunoreceptor NKG2D but not CD4+ T cells.

View Article: PubMed Central - PubMed

Affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom.

Show MeSH
Related in: MedlinePlus