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 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.
Demehri
Shadmehr
S
Department of Developmental Biology and Division of Dermatology, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
Morimoto
Mitsuru
M
Holtzman
Michael J
MJ
Kopan
Raphael
R
D000818:Animals; D001249:Asthma / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism*; D003876:Dermatitis, Atopic / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D012867:Skin / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497571:Rbpj protein, mouse; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse