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Skin barrier homeostasis in atopic dermatitis: feedback regulation of kallikrein activity.

Tanaka RJ, Ono M, Harrington HA - PLoS ONE (2011)

Bottom Line: Our models predicted the outbreaks of inflammation at weaker stimulus and its longer persistence in AD patients compared to healthy control.Our results strongly implicate the presence and importance of feedback mechanisms in KLK activity regulation.We further proposed future experiments that may provide informative data to enhance the system-level understanding on the regulatory mechanisms of skin barrier in AD and healthy individuals.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, Imperial College London, London, United Kingdom. r.tanaka@imperial.ac.uk

ABSTRACT
Atopic dermatitis (AD) is a widely spread cutaneous chronic disease characterised by sensitive reactions (eg. eczema) to normally innocuous elements. Although relatively little is understood about its underlying mechanisms due to its complexity, skin barrier dysfunction has been recognised as a key factor in the development of AD. Skin barrier homeostasis requires tight control of the activity of proteases, called kallikreins (KLKs), whose activity is regulated by a complex network of protein interactions that remains poorly understood despite its pathological importance. Characteristic symptoms of AD include the outbreak of inflammation triggered by external (eg. mechanical and chemical) stimulus and the persistence and aggravation of inflammation even if the initial stimulus disappears. These characteristic symptoms, together with some experimental data, suggest the presence of positive feedback regulation for KLK activity by inflammatory signals. We developed simple mathematical models for the KLK activation system to study the effects of feedback loops and carried out bifurcation analysis to investigate the model behaviours corresponding to inflammation caused by external stimulus. The model analysis confirmed that the hypothesised core model mechanisms capture the essence of inflammation outbreak by a defective skin barrier. Our models predicted the outbreaks of inflammation at weaker stimulus and its longer persistence in AD patients compared to healthy control. We also proposed a novel quantitative indicator for inflammation level by applying principal component analysis to microarray data. The model analysis reproduced qualitative AD characteristics revealed by this indicator. Our results strongly implicate the presence and importance of feedback mechanisms in KLK activity regulation. We further proposed future experiments that may provide informative data to enhance the system-level understanding on the regulatory mechanisms of skin barrier in AD and healthy individuals.

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Microarray data for AD and HC samples.PAR2 score was derived using the data [34] of seven PAR2 downstream genes (see Methods). PAR2 score is plotted against expression data [34] of (A) KLK5, (B) SPINK5, and (C) KLK7 for lesional AD (red squares), non-lesional AD (blue squares), and HC (black circles). The dotted lines indicate the median values of HC samples.
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pone-0019895-g007: Microarray data for AD and HC samples.PAR2 score was derived using the data [34] of seven PAR2 downstream genes (see Methods). PAR2 score is plotted against expression data [34] of (A) KLK5, (B) SPINK5, and (C) KLK7 for lesional AD (red squares), non-lesional AD (blue squares), and HC (black circles). The dotted lines indicate the median values of HC samples.

Mentions: The calculated PAR2 score was plotted against the expression data of KLK5, SPINK5 (encoding LEKTI), and KLK7 in Fig. 7 for LAD (red squares), NLAD (blue squares), and HC (black circles). The dotted lines indicate the median of HC data that provides the reference value. Due to the small number of data and the individual variability, we are mostly concerned with whether the data value is high or low relative to the reference. Most of LAD and some of NLAD show high PAR2 score suggesting that inflammatory processes occur at certain degrees in these skin samples, whereas all of HC show low PAR2 scores, which reflect the absence of inflammation and are considered to be a background level in this analysis. This confirms that the PAR2 score calculated here is a reasonable indicator for the inflammation level.


Skin barrier homeostasis in atopic dermatitis: feedback regulation of kallikrein activity.

Tanaka RJ, Ono M, Harrington HA - PLoS ONE (2011)

Microarray data for AD and HC samples.PAR2 score was derived using the data [34] of seven PAR2 downstream genes (see Methods). PAR2 score is plotted against expression data [34] of (A) KLK5, (B) SPINK5, and (C) KLK7 for lesional AD (red squares), non-lesional AD (blue squares), and HC (black circles). The dotted lines indicate the median values of HC samples.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102059&req=5

pone-0019895-g007: Microarray data for AD and HC samples.PAR2 score was derived using the data [34] of seven PAR2 downstream genes (see Methods). PAR2 score is plotted against expression data [34] of (A) KLK5, (B) SPINK5, and (C) KLK7 for lesional AD (red squares), non-lesional AD (blue squares), and HC (black circles). The dotted lines indicate the median values of HC samples.
Mentions: The calculated PAR2 score was plotted against the expression data of KLK5, SPINK5 (encoding LEKTI), and KLK7 in Fig. 7 for LAD (red squares), NLAD (blue squares), and HC (black circles). The dotted lines indicate the median of HC data that provides the reference value. Due to the small number of data and the individual variability, we are mostly concerned with whether the data value is high or low relative to the reference. Most of LAD and some of NLAD show high PAR2 score suggesting that inflammatory processes occur at certain degrees in these skin samples, whereas all of HC show low PAR2 scores, which reflect the absence of inflammation and are considered to be a background level in this analysis. This confirms that the PAR2 score calculated here is a reasonable indicator for the inflammation level.

Bottom Line: Our models predicted the outbreaks of inflammation at weaker stimulus and its longer persistence in AD patients compared to healthy control.Our results strongly implicate the presence and importance of feedback mechanisms in KLK activity regulation.We further proposed future experiments that may provide informative data to enhance the system-level understanding on the regulatory mechanisms of skin barrier in AD and healthy individuals.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, Imperial College London, London, United Kingdom. r.tanaka@imperial.ac.uk

ABSTRACT
Atopic dermatitis (AD) is a widely spread cutaneous chronic disease characterised by sensitive reactions (eg. eczema) to normally innocuous elements. Although relatively little is understood about its underlying mechanisms due to its complexity, skin barrier dysfunction has been recognised as a key factor in the development of AD. Skin barrier homeostasis requires tight control of the activity of proteases, called kallikreins (KLKs), whose activity is regulated by a complex network of protein interactions that remains poorly understood despite its pathological importance. Characteristic symptoms of AD include the outbreak of inflammation triggered by external (eg. mechanical and chemical) stimulus and the persistence and aggravation of inflammation even if the initial stimulus disappears. These characteristic symptoms, together with some experimental data, suggest the presence of positive feedback regulation for KLK activity by inflammatory signals. We developed simple mathematical models for the KLK activation system to study the effects of feedback loops and carried out bifurcation analysis to investigate the model behaviours corresponding to inflammation caused by external stimulus. The model analysis confirmed that the hypothesised core model mechanisms capture the essence of inflammation outbreak by a defective skin barrier. Our models predicted the outbreaks of inflammation at weaker stimulus and its longer persistence in AD patients compared to healthy control. We also proposed a novel quantitative indicator for inflammation level by applying principal component analysis to microarray data. The model analysis reproduced qualitative AD characteristics revealed by this indicator. Our results strongly implicate the presence and importance of feedback mechanisms in KLK activity regulation. We further proposed future experiments that may provide informative data to enhance the system-level understanding on the regulatory mechanisms of skin barrier in AD and healthy individuals.

Show MeSH
Related in: MedlinePlus