Limits...
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.

Show MeSH

Related in: MedlinePlus

Models of skin desquamation.A: Cartoon model of skin desquamation. Skin barrier is physically composed of the cornified layer, where keratin-filled and anucleated keratinocytes (corneocytes) are densely packed with skin lipids. Corneocytes are interconnected by corneodesmosomes. Skin desquamation occurs by elimination of corneocytes at the skin surface. B: Cartoon model of protein interactions involved in KLK5 activation regulation. (a) KLK5 and their inhibitor LEKTI are secreted from granular cells into the intercellular space at the interface of cornified and granular layers; (b) KLK5 self-activates by proteolysis; (c) Direct binding of LEKTI inhibits the activity of KLK5; (d) Active KLK5 physically cleaves corneodesmosomes, which bind corneocytes together, resulting in elimination of corneocytes; (e) PAR2 is cleaved by active KLK5 to be activated and internalized. Figure was modified from [9]. C: Simplified model for KLK5 activation regulation system proposed in this paper. KLK5* and PAR2* represent the activated forms of KLK5 and PAR2, respectively. (a) KLK5 self-activation by proteolysis; (b) Association and dissociation of LEKTI and KLK5*; (c) PAR2 activation by KLK5*; (d) Feedback from PAR2* to production of LEKTI (); (e) Feedback from PAR2* to production of KLK5 (); Inflammation level is denoted by the level of PAR2*.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3102059&req=5

pone-0019895-g001: Models of skin desquamation.A: Cartoon model of skin desquamation. Skin barrier is physically composed of the cornified layer, where keratin-filled and anucleated keratinocytes (corneocytes) are densely packed with skin lipids. Corneocytes are interconnected by corneodesmosomes. Skin desquamation occurs by elimination of corneocytes at the skin surface. B: Cartoon model of protein interactions involved in KLK5 activation regulation. (a) KLK5 and their inhibitor LEKTI are secreted from granular cells into the intercellular space at the interface of cornified and granular layers; (b) KLK5 self-activates by proteolysis; (c) Direct binding of LEKTI inhibits the activity of KLK5; (d) Active KLK5 physically cleaves corneodesmosomes, which bind corneocytes together, resulting in elimination of corneocytes; (e) PAR2 is cleaved by active KLK5 to be activated and internalized. Figure was modified from [9]. C: Simplified model for KLK5 activation regulation system proposed in this paper. KLK5* and PAR2* represent the activated forms of KLK5 and PAR2, respectively. (a) KLK5 self-activation by proteolysis; (b) Association and dissociation of LEKTI and KLK5*; (c) PAR2 activation by KLK5*; (d) Feedback from PAR2* to production of LEKTI (); (e) Feedback from PAR2* to production of KLK5 (); Inflammation level is denoted by the level of PAR2*.

Mentions: The skin barrier is physically composed of the cornified layer, where keratin-filled and anucleated keratinocytes (corneocytes) are densely packed with skin lipids (Fig. 1A). Skin barrier homeostasis is attained by balancing the differentiation of granular layer keratinocytes to corneocytes against elimination of corneocytes at the skin surface (desquamation) [6]. The latter occurs as the result of cleavage of corneodesmosomes (Fig. 1B), which bind corneocytes together, by serine proteases called kallikreins (KLKs) [7]. Excessive activities of KLKs can impair the skin barrier via premature breakdown of corneodesmosomes by KLKs [8] and increase corneocyte desquamation. Accumulating evidence indicates malfunctions in the spatial and temporal control of KLK activity in AD patients is one of the main causes for their defective skin barrier homeostasis [9].


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

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

Models of skin desquamation.A: Cartoon model of skin desquamation. Skin barrier is physically composed of the cornified layer, where keratin-filled and anucleated keratinocytes (corneocytes) are densely packed with skin lipids. Corneocytes are interconnected by corneodesmosomes. Skin desquamation occurs by elimination of corneocytes at the skin surface. B: Cartoon model of protein interactions involved in KLK5 activation regulation. (a) KLK5 and their inhibitor LEKTI are secreted from granular cells into the intercellular space at the interface of cornified and granular layers; (b) KLK5 self-activates by proteolysis; (c) Direct binding of LEKTI inhibits the activity of KLK5; (d) Active KLK5 physically cleaves corneodesmosomes, which bind corneocytes together, resulting in elimination of corneocytes; (e) PAR2 is cleaved by active KLK5 to be activated and internalized. Figure was modified from [9]. C: Simplified model for KLK5 activation regulation system proposed in this paper. KLK5* and PAR2* represent the activated forms of KLK5 and PAR2, respectively. (a) KLK5 self-activation by proteolysis; (b) Association and dissociation of LEKTI and KLK5*; (c) PAR2 activation by KLK5*; (d) Feedback from PAR2* to production of LEKTI (); (e) Feedback from PAR2* to production of KLK5 (); Inflammation level is denoted by the level of PAR2*.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0019895-g001: Models of skin desquamation.A: Cartoon model of skin desquamation. Skin barrier is physically composed of the cornified layer, where keratin-filled and anucleated keratinocytes (corneocytes) are densely packed with skin lipids. Corneocytes are interconnected by corneodesmosomes. Skin desquamation occurs by elimination of corneocytes at the skin surface. B: Cartoon model of protein interactions involved in KLK5 activation regulation. (a) KLK5 and their inhibitor LEKTI are secreted from granular cells into the intercellular space at the interface of cornified and granular layers; (b) KLK5 self-activates by proteolysis; (c) Direct binding of LEKTI inhibits the activity of KLK5; (d) Active KLK5 physically cleaves corneodesmosomes, which bind corneocytes together, resulting in elimination of corneocytes; (e) PAR2 is cleaved by active KLK5 to be activated and internalized. Figure was modified from [9]. C: Simplified model for KLK5 activation regulation system proposed in this paper. KLK5* and PAR2* represent the activated forms of KLK5 and PAR2, respectively. (a) KLK5 self-activation by proteolysis; (b) Association and dissociation of LEKTI and KLK5*; (c) PAR2 activation by KLK5*; (d) Feedback from PAR2* to production of LEKTI (); (e) Feedback from PAR2* to production of KLK5 (); Inflammation level is denoted by the level of PAR2*.
Mentions: The skin barrier is physically composed of the cornified layer, where keratin-filled and anucleated keratinocytes (corneocytes) are densely packed with skin lipids (Fig. 1A). Skin barrier homeostasis is attained by balancing the differentiation of granular layer keratinocytes to corneocytes against elimination of corneocytes at the skin surface (desquamation) [6]. The latter occurs as the result of cleavage of corneodesmosomes (Fig. 1B), which bind corneocytes together, by serine proteases called kallikreins (KLKs) [7]. Excessive activities of KLKs can impair the skin barrier via premature breakdown of corneodesmosomes by KLKs [8] and increase corneocyte desquamation. Accumulating evidence indicates malfunctions in the spatial and temporal control of KLK activity in AD patients is one of the main causes for their defective skin barrier homeostasis [9].

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