Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma.

Asthma is a common allergic lung disease frequently affecting individuals with a prior history of eczema/atopic dermatitis (AD); however, the mechanism underlying the progression from AD to asthma (the so-called "atopic march") is unclear. Here we show that, like humans with AD, mice with...

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Autores principales:	Shadmehr Demehri, Mitsuru Morimoto, Michael J Holtzman, Raphael Kopan
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/71df762ecb14474ca89534d3d02d348d
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spelling	oai:doaj.org-article:71df762ecb14474ca89534d3d02d348d2021-11-25T05:34:11ZSkin-derived TSLP triggers progression from epidermal-barrier defects to asthma.1544-91731545-788510.1371/journal.pbio.1000067https://doaj.org/article/71df762ecb14474ca89534d3d02d348d2009-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19557146/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Asthma is a common allergic lung disease frequently affecting individuals with a prior history of eczema/atopic dermatitis (AD); however, the mechanism underlying the progression from AD to asthma (the so-called "atopic march") is unclear. Here we show that, like humans with AD, mice with skin-barrier defects develop AD-like skin inflammation and are susceptible to allergic asthma. Furthermore, we show that thymic stromal lymphopoietin (TSLP), overexpressed by skin keratinocytes, is the systemic driver of this bronchial hyper-responsiveness. As an AD-like model, we used mice with keratinocyte-specific deletion of RBP-j that sustained high systemic levels of TSLP. Antigen-induced allergic challenge to the lung airways of RBP-j-deficient animals resulted in a severe asthmatic phenotype not seen in similarly treated wild-type littermates. Elimination of TSLP signaling in these animals blocked the atopic march, demonstrating that high serum TSLP levels were required to sensitize the lung to allergic inflammation. Furthermore, we analyzed outbred K14-TSLP(tg) mice that maintained high systemic levels of TSLP without developing any skin pathology. Importantly, epidermal-derived TSLP was sufficient to trigger the atopic march, sensitizing the lung airways to inhaled allergens in the absence of epicutaneous sensitization. Based on these findings, we propose that in addition to early treatment of the primary skin-barrier defects, selective inhibition of systemic TSLP may be the key to blocking the development of asthma in AD patients.Shadmehr DemehriMitsuru MorimotoMichael J HoltzmanRaphael KopanPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 7, Iss 5, p e1000067 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Shadmehr Demehri Mitsuru Morimoto Michael J Holtzman Raphael Kopan Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma.
description	Asthma is a common allergic lung disease frequently affecting individuals with a prior history of eczema/atopic dermatitis (AD); however, the mechanism underlying the progression from AD to asthma (the so-called "atopic march") is unclear. Here we show that, like humans with AD, mice with skin-barrier defects develop AD-like skin inflammation and are susceptible to allergic asthma. Furthermore, we show that thymic stromal lymphopoietin (TSLP), overexpressed by skin keratinocytes, is the systemic driver of this bronchial hyper-responsiveness. As an AD-like model, we used mice with keratinocyte-specific deletion of RBP-j that sustained high systemic levels of TSLP. Antigen-induced allergic challenge to the lung airways of RBP-j-deficient animals resulted in a severe asthmatic phenotype not seen in similarly treated wild-type littermates. Elimination of TSLP signaling in these animals blocked the atopic march, demonstrating that high serum TSLP levels were required to sensitize the lung to allergic inflammation. Furthermore, we analyzed outbred K14-TSLP(tg) mice that maintained high systemic levels of TSLP without developing any skin pathology. Importantly, epidermal-derived TSLP was sufficient to trigger the atopic march, sensitizing the lung airways to inhaled allergens in the absence of epicutaneous sensitization. Based on these findings, we propose that in addition to early treatment of the primary skin-barrier defects, selective inhibition of systemic TSLP may be the key to blocking the development of asthma in AD patients.
format	article
author	Shadmehr Demehri Mitsuru Morimoto Michael J Holtzman Raphael Kopan
author_facet	Shadmehr Demehri Mitsuru Morimoto Michael J Holtzman Raphael Kopan
author_sort	Shadmehr Demehri
title	Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma.
title_short	Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma.
title_full	Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma.
title_fullStr	Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma.
title_full_unstemmed	Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma.
title_sort	skin-derived tslp triggers progression from epidermal-barrier defects to asthma.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/71df762ecb14474ca89534d3d02d348d
work_keys_str_mv	AT shadmehrdemehri skinderivedtslptriggersprogressionfromepidermalbarrierdefectstoasthma AT mitsurumorimoto skinderivedtslptriggersprogressionfromepidermalbarrierdefectstoasthma AT michaeljholtzman skinderivedtslptriggersprogressionfromepidermalbarrierdefectstoasthma AT raphaelkopan skinderivedtslptriggersprogressionfromepidermalbarrierdefectstoasthma
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Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma.

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