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A breakthrough in understanding the mechanisms of inflammatory skin diseases

Schematic Yin-yang representation showing that the outcome of skin inflammation upon the breakdown of epidermal stratum corneum (SC) barrier is shaped by the counter-regulation between TSLP-driven type 2 immune axis and IL-23-driven type 17 immune axis, which are both under the control of IL-1β.

Counterregulation between thymic stromal lymphopoietin- and IL-23-driven immune axes shapes skin inflammation in mice with epidermal barrier defects.

Li J(1), Leyva-Castillo JM(1), Hener P(1), Eisenmann A(1), Zaafouri S(2), Jonca N(2), Serre G(2), Birling MC(3), Li M(4).

J Allergy Clin Immunol Jul 2016

March 15, 2016

The skin ensures, through the stratum corneum of the epidermis, its vital function as a protective barrier for our body. Dysfunction of stratum corneum barrier leads to various skin inflammatory pathologies. Mei LI’s team from the IGBMC, in collaboration with ICS and the University of Toulouse III, has revealed that the inflammation developed on barrier-defective skin is shaped by two immune axes that counteract each other. It also showed that blockade of interleukin 1 signaling effectively suppresses both inflammatory axes and ameliorates skin inflammation. These results were published in The Journal of Allergy and Clinical Immunology, on March 15th 2016.



The skin epidermis functions as a primary defense and biosensor to the external environment. Dysfunction of the epidermal barrier, resulting from various abnormalities in the stratum corneum (SC), has emerged as a critical factor in initiating and exacerbating skin inflammation, particularly in atopic dermatitis (AD), as well as AD-like congenital disorders including type B generalized peeling skin syndrome (PSS-B) and netherton syndrome (NS). These diseases all exhibit eczematoid cutaneous inflammation, associated with frequent bacterial colonization.

Studies on the inflammatory responses in barrier-defective skin have generated controversial data in both humans and mice. A new study of the team of Mei Li in IGBMC deciphers the inflammatory axes and cytokine network in mouse skin during breakdown of epidermal SC barrier, thus providing novel insights into how the inflammatory phenotype in barrier-defective skin is shaped by two seemingly counteracting immune axes. These results are now published on March 15th 2016 in The Journal of Allergy and Clinical Immunology.


Deciphering the inflammatory mechanisms in skin with epidermal barrier defects


In this study, researchers generated a mouse model in which they knocked out a critical barrier gene called CDSN selectively in epidermal keratinocytes in an inducible manner. This gene encodes corneodesmosin, a structural protein of corneodesmosomes, structures that mediate adhesion of the intercorneocyte cells in the SC. Targeting of this gene is based on the fact that CDSN mutations have been recently identified in PSS-B patients. This model allowed the researchers to analyze the dynamics of skin inflammation on breakdown of the epidermal barrier, and to further dissect the cytokine network underlying the inflammatory process. By combining genetic tools, antibody-mediated neutralization, signaling blocking reagents with histological analyses and molecular biology approaches, the authors showed that barrier-defective skin develops type 2 and type 17 inflammatory responses, which are driven by cytokines thymic stromal lymphopoietin (TSLP) and IL-23, respectively (See Figure). They also demonstrated that the induction of TSLP is mediated by protease activation receptor PAR-2 signaling, while the expression of IL-23 is induced by skin bacteria flora. Mechnistically, the TSLP/type 2 and the IL-23/type-17 immune axes counter regulate each other while interleukin-1β plays a critical role in regulating the expression of TSLP and IL-23.


Insights into future therapeutic treatments


While the current study bases on the mouse model of PSS-B, the researchers believe that the counter-regulation of TSLP/type 2 and Il-23/type 17 represents a mechanism underlying the complexity and heterogeneity of inflammatory phenotype implicated in AD and AD-like congenital diseases. Also of importance is the clinical relevance of this study. The authors show that blockade of IL-1 signaling by Anakinra, a recombinant IL-1 receptor antagonist clinically used for rheumatoid arthritis, suppresses both TSLP and IL-23 expression and ameliorates the skin inflammation; therefore, the authors propose that targeting IL-1 is more advantageous than targeting the individual TSLP- or IL-23-axis, and may have broad potential for the treatment of various inflammatory skin diseases related to epidermal barrier defects.

Imprimer Envoyer

Université de Strasbourg

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