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Counterregulation between thymic stromal lymphopoietin- and IL-23-driven immune axes shapes skin inflammation in mice with epidermal barrier defects.
J Allergy Clin Immunol 2016; 138(1):150-161.e13JA

Abstract

BACKGROUND

Epidermal barrier dysfunction has been recognized as a critical factor in the initiation and exacerbation of skin inflammation, particularly in patients with atopic dermatitis (AD) and AD-like congenital disorders, including peeling skin syndrome type B. However, inflammatory responses developed in barrier-defective skin, as well as the underlying mechanisms, remained incompletely understood.

OBJECTIVE

We aimed to decipher inflammatory axes and the cytokine network in mouse skin on breakdown of epidermal stratum corneum barrier.

METHODS

We generated Cdsn(iep-/-) mice with corneodesmosin ablation in keratinocytes selectively in an inducible manner. We characterized inflammatory responses and cytokine expression by using histology, immunohistochemistry, ELISA, and quantitative PCR. We combined mouse genetic tools, antibody-mediated neutralization, signal-blocking reagents, and topical antibiotic treatment to explore the inflammatory axes.

RESULTS

We show that on breakdown of the epidermal stratum corneum barrier, type 2 and type 17 inflammatory responses are developed simultaneously, driven by thymic stromal lymphopoietin (TSLP) and IL-23, respectively. Importantly, we reveal a counterregulation between these 2 inflammatory axes. Furthermore, we show that protease-activated receptor 2 signaling is involved in mediating the TSLP/type 2 axis, whereas skin bacteria are engaged in induction of the IL-23/type 17 axis. Moreover, we find that IL-1β is induced in skin of Cdsn(iep-/-) mice and that blockade of IL-1 signaling suppresses both TSLP and IL-23 expression and ameliorates skin inflammation.

CONCLUSION

The inflammatory phenotype in barrier-defective skin is shaped by counterregulation between the TSLP/type 2 and IL-23/type 17 axes. Targeting IL-1 signaling could be a promising therapeutic option for controlling skin inflammation in patients with peeling skin syndrome type B and other diseases related to epidermal barrier dysfunction, including AD.

Authors+Show Affiliations

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique UMR7104/Institut National de la Santé et de la Recherche Médicale U964/Université de Strasbourg, Illkirch, France.Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique UMR7104/Institut National de la Santé et de la Recherche Médicale U964/Université de Strasbourg, Illkirch, France.Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique UMR7104/Institut National de la Santé et de la Recherche Médicale U964/Université de Strasbourg, Illkirch, France.Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique UMR7104/Institut National de la Santé et de la Recherche Médicale U964/Université de Strasbourg, Illkirch, France.Différenciation Epidermique et Autoimmunité Rhumatoïde, Centre National de la Recherche Scientifique UMR5165/Institut National de la Recherche Médicale U1056/Université Toulouse III, Hôpital Purpan, Toulouse, France.Différenciation Epidermique et Autoimmunité Rhumatoïde, Centre National de la Recherche Scientifique UMR5165/Institut National de la Recherche Médicale U1056/Université Toulouse III, Hôpital Purpan, Toulouse, France.Différenciation Epidermique et Autoimmunité Rhumatoïde, Centre National de la Recherche Scientifique UMR5165/Institut National de la Recherche Médicale U1056/Université Toulouse III, Hôpital Purpan, Toulouse, France.Institut Clinique de la Souris, Illkirch, France.Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique UMR7104/Institut National de la Santé et de la Recherche Médicale U964/Université de Strasbourg, Illkirch, France; University of Strasbourg Institute for Advanced Study, Strasbourg, France; Freiburg Institute for Advanced Studies, Freiburg, Germany. Electronic address: mei@igbmc.fr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26993035

Citation

Li, Jiagui, et al. "Counterregulation Between Thymic Stromal Lymphopoietin- and IL-23-driven Immune Axes Shapes Skin Inflammation in Mice With Epidermal Barrier Defects." The Journal of Allergy and Clinical Immunology, vol. 138, no. 1, 2016, pp. 150-161.e13.
Li J, Leyva-Castillo JM, Hener P, et al. Counterregulation between thymic stromal lymphopoietin- and IL-23-driven immune axes shapes skin inflammation in mice with epidermal barrier defects. J Allergy Clin Immunol. 2016;138(1):150-161.e13.
Li, J., Leyva-Castillo, J. M., Hener, P., Eisenmann, A., Zaafouri, S., Jonca, N., ... Li, M. (2016). Counterregulation between thymic stromal lymphopoietin- and IL-23-driven immune axes shapes skin inflammation in mice with epidermal barrier defects. The Journal of Allergy and Clinical Immunology, 138(1), pp. 150-161.e13. doi:10.1016/j.jaci.2016.01.013.
Li J, et al. Counterregulation Between Thymic Stromal Lymphopoietin- and IL-23-driven Immune Axes Shapes Skin Inflammation in Mice With Epidermal Barrier Defects. J Allergy Clin Immunol. 2016;138(1):150-161.e13. PubMed PMID: 26993035.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Counterregulation between thymic stromal lymphopoietin- and IL-23-driven immune axes shapes skin inflammation in mice with epidermal barrier defects. AU - Li,Jiagui, AU - Leyva-Castillo,Juan Manuel, AU - Hener,Pierre, AU - Eisenmann,Aurelie, AU - Zaafouri,Sarra, AU - Jonca,Nathalie, AU - Serre,Guy, AU - Birling,Marie-Christine, AU - Li,Mei, Y1 - 2016/03/15/ PY - 2015/03/31/received PY - 2016/01/11/revised PY - 2016/01/22/accepted PY - 2016/3/20/entrez PY - 2016/3/20/pubmed PY - 2017/6/16/medline KW - Epidermal barrier KW - IL-1β KW - IL-23 KW - T(H)17 KW - T(H)2 KW - atopic dermatitis KW - corneodesmosin KW - mouse model KW - peeling skin syndrome type B KW - skin inflammation KW - thymic stromal lymphopoietin SP - 150 EP - 161.e13 JF - The Journal of allergy and clinical immunology JO - J. Allergy Clin. Immunol. VL - 138 IS - 1 N2 - BACKGROUND: Epidermal barrier dysfunction has been recognized as a critical factor in the initiation and exacerbation of skin inflammation, particularly in patients with atopic dermatitis (AD) and AD-like congenital disorders, including peeling skin syndrome type B. However, inflammatory responses developed in barrier-defective skin, as well as the underlying mechanisms, remained incompletely understood. OBJECTIVE: We aimed to decipher inflammatory axes and the cytokine network in mouse skin on breakdown of epidermal stratum corneum barrier. METHODS: We generated Cdsn(iep-/-) mice with corneodesmosin ablation in keratinocytes selectively in an inducible manner. We characterized inflammatory responses and cytokine expression by using histology, immunohistochemistry, ELISA, and quantitative PCR. We combined mouse genetic tools, antibody-mediated neutralization, signal-blocking reagents, and topical antibiotic treatment to explore the inflammatory axes. RESULTS: We show that on breakdown of the epidermal stratum corneum barrier, type 2 and type 17 inflammatory responses are developed simultaneously, driven by thymic stromal lymphopoietin (TSLP) and IL-23, respectively. Importantly, we reveal a counterregulation between these 2 inflammatory axes. Furthermore, we show that protease-activated receptor 2 signaling is involved in mediating the TSLP/type 2 axis, whereas skin bacteria are engaged in induction of the IL-23/type 17 axis. Moreover, we find that IL-1β is induced in skin of Cdsn(iep-/-) mice and that blockade of IL-1 signaling suppresses both TSLP and IL-23 expression and ameliorates skin inflammation. CONCLUSION: The inflammatory phenotype in barrier-defective skin is shaped by counterregulation between the TSLP/type 2 and IL-23/type 17 axes. Targeting IL-1 signaling could be a promising therapeutic option for controlling skin inflammation in patients with peeling skin syndrome type B and other diseases related to epidermal barrier dysfunction, including AD. SN - 1097-6825 UR - https://www.unboundmedicine.com/medline/citation/26993035/Counterregulation_between_thymic_stromal_lymphopoietin__and_IL_23_driven_immune_axes_shapes_skin_inflammation_in_mice_with_epidermal_barrier_defects_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-6749(16)00190-1 DB - PRIME DP - Unbound Medicine ER -