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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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Keratinocyte responses to TPA treatment.(A) H&E stained skin sections of mice treated three times with acetone or TPA. Asterisk: neutrophil containing pustule; white arrow: spongiosis; black arrow: parakeratosis. % hyperkeratotic (B) and parakeratotic (C) stratum corneum (8 cm skin analysed per condition). (D) Epidermal thickness in μm (8 cm skin analysed per condition). (E–G) Number of epidermal cells positively labeled for PH3 (E), γH2AX (F) and active caspase-3 (G) per cm skin (7 cm skin analysed per condition). (H) Number of BrdU positive cells in basal and uppermost two granular layers per cm epidermis of mice treated three times with TPA and injected with BrdU 24 hr before harvesting. Data from all graphs represent means ± SEM from at least four mice per genotype. Scale bar: 100 μm.DOI:http://dx.doi.org/10.7554/eLife.01888.005
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fig3: Keratinocyte responses to TPA treatment.(A) H&E stained skin sections of mice treated three times with acetone or TPA. Asterisk: neutrophil containing pustule; white arrow: spongiosis; black arrow: parakeratosis. % hyperkeratotic (B) and parakeratotic (C) stratum corneum (8 cm skin analysed per condition). (D) Epidermal thickness in μm (8 cm skin analysed per condition). (E–G) Number of epidermal cells positively labeled for PH3 (E), γH2AX (F) and active caspase-3 (G) per cm skin (7 cm skin analysed per condition). (H) Number of BrdU positive cells in basal and uppermost two granular layers per cm epidermis of mice treated three times with TPA and injected with BrdU 24 hr before harvesting. Data from all graphs represent means ± SEM from at least four mice per genotype. Scale bar: 100 μm.DOI:http://dx.doi.org/10.7554/eLife.01888.005

Mentions: EPI−/− mice exhibited an exacerbated response to TPA (Figure 3A). Their skin was reddened, dry and scaly, whereas that of WT mice was not (data not shown). Histological analysis revealed increased hyperkeratosis (thickened stratum corneum) and parakeratosis (retention of nuclei in cornified cells) (Figure 3B,C), consistent with defective desquamation (Sevilla et al., 2007). Widening of intercellular spaces in the epidermal basal layer (spongiosis) was extensive in EPI−/− but not WT skin (Figure 3A). Epidermal thickness, measured as the distance from the basal to the upper granular layer, was greater in EPI−/− mice treated with TPA or DMBA/TPA than in WT mice, and this correlated with a greater number of suprabasal layers (Figure 3A,D). The numbers of keratinocytes with dsDNA breaks and active caspase-3 were similar in EPI−/− and WT epidermis (Figure 3F,G).10.7554/eLife.01888.005Figure 3.Keratinocyte responses to TPA treatment.


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

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

Keratinocyte responses to TPA treatment.(A) H&E stained skin sections of mice treated three times with acetone or TPA. Asterisk: neutrophil containing pustule; white arrow: spongiosis; black arrow: parakeratosis. % hyperkeratotic (B) and parakeratotic (C) stratum corneum (8 cm skin analysed per condition). (D) Epidermal thickness in μm (8 cm skin analysed per condition). (E–G) Number of epidermal cells positively labeled for PH3 (E), γH2AX (F) and active caspase-3 (G) per cm skin (7 cm skin analysed per condition). (H) Number of BrdU positive cells in basal and uppermost two granular layers per cm epidermis of mice treated three times with TPA and injected with BrdU 24 hr before harvesting. Data from all graphs represent means ± SEM from at least four mice per genotype. Scale bar: 100 μm.DOI:http://dx.doi.org/10.7554/eLife.01888.005
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4007207&req=5

fig3: Keratinocyte responses to TPA treatment.(A) H&E stained skin sections of mice treated three times with acetone or TPA. Asterisk: neutrophil containing pustule; white arrow: spongiosis; black arrow: parakeratosis. % hyperkeratotic (B) and parakeratotic (C) stratum corneum (8 cm skin analysed per condition). (D) Epidermal thickness in μm (8 cm skin analysed per condition). (E–G) Number of epidermal cells positively labeled for PH3 (E), γH2AX (F) and active caspase-3 (G) per cm skin (7 cm skin analysed per condition). (H) Number of BrdU positive cells in basal and uppermost two granular layers per cm epidermis of mice treated three times with TPA and injected with BrdU 24 hr before harvesting. Data from all graphs represent means ± SEM from at least four mice per genotype. Scale bar: 100 μm.DOI:http://dx.doi.org/10.7554/eLife.01888.005
Mentions: EPI−/− mice exhibited an exacerbated response to TPA (Figure 3A). Their skin was reddened, dry and scaly, whereas that of WT mice was not (data not shown). Histological analysis revealed increased hyperkeratosis (thickened stratum corneum) and parakeratosis (retention of nuclei in cornified cells) (Figure 3B,C), consistent with defective desquamation (Sevilla et al., 2007). Widening of intercellular spaces in the epidermal basal layer (spongiosis) was extensive in EPI−/− but not WT skin (Figure 3A). Epidermal thickness, measured as the distance from the basal to the upper granular layer, was greater in EPI−/− mice treated with TPA or DMBA/TPA than in WT mice, and this correlated with a greater number of suprabasal layers (Figure 3A,D). The numbers of keratinocytes with dsDNA breaks and active caspase-3 were similar in EPI−/− and WT epidermis (Figure 3F,G).10.7554/eLife.01888.005Figure 3.Keratinocyte responses to TPA treatment.

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