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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Public Library of Science (PLoS)
2009-05-01
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| Series: | PLoS Biology |
| Online Access: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.1000067&type=printable |
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| 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 |
| collection | DOAJ |
| 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 |
| id | doaj-art-71df762ecb14474ca89534d3d02d348d |
| institution | DOAJ |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2009-05-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Biology |
| spelling | doaj-art-71df762ecb14474ca89534d3d02d348d2025-08-20T03:22:35ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852009-05-0175e100006710.1371/journal.pbio.1000067Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma.Shadmehr DemehriMitsuru MorimotoMichael J HoltzmanRaphael KopanAsthma 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.https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.1000067&type=printable |
| spellingShingle | Shadmehr Demehri Mitsuru Morimoto Michael J Holtzman Raphael Kopan Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma. PLoS Biology |
| title | 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_short | Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma. |
| title_sort | skin derived tslp triggers progression from epidermal barrier defects to asthma |
| url | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.1000067&type=printable |
| work_keys_str_mv | AT shadmehrdemehri skinderivedtslptriggersprogressionfromepidermalbarrierdefectstoasthma AT mitsurumorimoto skinderivedtslptriggersprogressionfromepidermalbarrierdefectstoasthma AT michaeljholtzman skinderivedtslptriggersprogressionfromepidermalbarrierdefectstoasthma AT raphaelkopan skinderivedtslptriggersprogressionfromepidermalbarrierdefectstoasthma |