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Title: Skin-Derived TSLP Triggers Progression from Epidermal-Barrier Defects to Asthma}
Article:
Abstract:
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-TSLPtg 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.
Introduction:
Allergic asthma is a chronic lung disease characterized by T-helper2( Th2) –mediated inflammation and airway obstruction in response to allergen exposure[1]. Asthma is an increasingly common disorder affecting more than 300 million individuals around the world[2]. Atopic dermatitis( AD) is another prevalent allergic disease, and 17% of children in the United States suffer from this disorder[3]. In comparison to its 4–8% prevalence in the general population, asthma develops in up to 70% of patients with history of severe AD, a phenomenon referred to as “atopic march”[3]. It may be possible to prevent asthma in these at-risk individuals by early diagnosis of AD and blockage of the atopic march. To achieve this, it is critical that we understand the mechanism triggering the development of asthma in AD patients. A survey of the literature has identified several possible mechanisms underlying the clinical link between AD and asthma. These include:( a) a systemic immune system disorder leading to excessive Th2 response at epithelial surfaces exposed to allergens[4],( b) a barrier defect shared by both skin and lung epithelia that leads to overstimulation of the immune cells by invading allergens[5], or( c) systemic consequences of a skin-specific barrier defect causing immune cells to mount an allergic inflammation at any allergen-exposed epithelial surface[6]. Epidemiological data supporting the third hypothesis include the observation that AD tends to be the first manifestation of the atopic march[3]. Another supportive observation relates to filaggrin, a skin cornified envelope protein that is absent from the lung epithelia[7],[8]. Although controversial[9], it seems that AD patients with filaggrin loss-of-function mutations exhibit increased incidence of asthma[10]–[12]. This is consistent with the third hypothesis, that loss of an epidermal-specific barrier protein can trigger systemic atopy in humans. Mechanistically, it is suspected that epicutaneous sensitization with allergens underlies the development of airway hyperreactivity in mice[13] and in humans with filaggrin mutations[10],[11]. However, it is unclear whether intrinsic skin-barrier defects can trigger asthma in the absence of any epicutaneous sensitization. If epicutaneous exposure is not required, it will imply that systemic factor( s) produced by AD skin may be involved in sensitizing the bronchial epithelia. Such factors will be important as therapeutic targets in preventing asthma. To address this question, we studied mice lacking Notch signaling in the skin. Skin keratinocytes are organized in highly interconnected basal, spinous, granular, and cornified layers, forming an elaborate barrier protecting the organism from the outside environment. One of the major molecular regulators of this structure is Notch signaling[14]–[16]. Notch is a transmembrane receptor interacting with ligands expressed on the surface of neighboring keratinocytes[16],[17]. Upon activation, sequential proteolysis of Notch releases its intracellular domain, which then translocates into the nucleus, binds to RBP-j( the DNA-binding partner of Notch), and activates downstream targets[17]. Keratinocyte-specific deletion of Notch signaling pathway components impairs epidermal differentiation, resulting in skin-barrier defects[15],[16]. We have recently shown that Notch signaling loss in the skin also triggers a severe neonatal B-lymphoproliferative disorder( B-LPD;[15]). This systemic disease is directly caused by elevated levels of thymic stromal lymphopoietin( TSLP) released into the circulation by Notch-deficient keratinocytes failing to differentiate[15]. TSLP, a general biomarker for skin-barrier defects[15], is an interleukin-7( IL-7) –like cytokine produced by epithelial cells and is implicated in the pathogenesis of both AD and asthma[18]–[22]. TSLP expression is sustained as long as barrier defects persist[15]. Thus, the potentially high systemic availability of skin-derived TSLP and its central role in promoting asthma bring up the possibility that TSLP may be the factor predisposing AD patients to asthma. Identifying a clear mechanism for the atopic march in the complex network of genetic, immunological, and environmental factors that contribute to AD has been a challenge to the field and has resulted in much debate as to the right therapeutic approach for preventing asthma[6]. To determine the mechanisms underlying the progression from AD to asthma, we first generated animals that lacked Notch signaling in a portion of their skin surfaces by embryonic removal of RBP-j from keratinocytes using the Msx2-Cre transgene( Msx2-Cre/+;RBP-jflox/flox or RBP-jCKO). Msx2-Cre is ectopically expressed at embryonic day 9. 5( E9. 5) in clusters of ectodermal cells, resulting in a chimeric pattern of RBP-j deletion in the skin[23]. The presence of unaffected skin surfaces allowed RBP-jCKO animals to live for approximately 100 days on average with a few surviving up to one year( Figure S1)[15],[16], presenting a model in which to determine whether a defective skin-barrier could cause AD-like symptoms and render susceptibility to asthma in the absence of epicutaneous sensitization. We found that defective skin-barrier function in adult RBP-j–deficient animals caused the development of an AD-like allergic inflammation and a subsequent susceptibility to asthma. To determine whether TSLP is required for this susceptibility, we deleted the TSLP receptor in RBP-jCKO mice and showed that this genetic manipulation blocked the development of asthma in animals with persistent AD-like pathology and inflammation. To ask if TSLP overexpression by skin keratinocytes is sufficient, we used outbred transgenic mice overexpressing TSLP in epidermal keratinocytes and showed that epidermal-derived TSLP was sufficient to confer a severe asthmatic phenotype even in the absence of any skin defect. These findings establish that high systemic availability of TSLP[15] can sensitize the lung to allergens, and provide a novel molecular mechanism for the atopic march. Serum TSLP is thus an important potential therapeutic target in preventing asthma in AD patients.
Discussion:
This report describes the mechanism that mediates the progression of a local allergic skin disease to a disseminated allergic inflammation downstream of skin-barrier defects in mice. We show that creating an intrinsic skin-barrier defect( by removing Notch signaling specifically from some skin keratinocytes) results in the sensitization of the lung airways to allergens. Similar to the clinical cases, barrier-defective mice require a secondary insult by allergens to expose their predisposition to asthma. Importantly, we show that epicutaneous sensitization with a common allergen[3] is not required to achieve this pronounced lung hyper-responsiveness. Therefore, RBP-jCKO animals demonstrate that skin-barrier impairment provides a signal that promotes development of a distant atopy in the lung, most likely by a systemic, diffusible cytokine. We identified this signal to be TSLP, a central player in the early stages of allergic inflammation[18]–[20] and a barrier-defect–sensitive product of skin keratinocytes that is released prior to development of an AD-like skin lesion[15]. In contrast to TSLP overexpression by lung epithelia, which does not result in systemic accumulation of this cytokine[18], overexpression of TSLP in the skin results in high systemic availability[15]. Therefore, skin is capable of acting as a signaling organ, driving susceptibility to allergic inflammation in another barrier organ( i. e., lung) by releasing TSLP. Importantly, we were able to show that TSLP was necessary to predispose RBP-j–deficient animals to the asthmatic phenotype. Concomitant removal of IL7Rα subunit of the TSLP receptor in RBP-jCKO mice prevented the atopic march despite persistent AD-like pathology and elevated serum IgE levels. Complementing this experiment is the observation that overexpression of TSLP by skin keratinocytes leads to high serum levels of TSLP that are sufficient to sensitize the lung airways to allergic inflammation in the absence of any skin pathology. If the low levels of TSLP in the trachea of K14-TSLPtg mice contribute to the phenotype, they do so by adding to the already high levels of skin-derived serum TSLP. Because TSLP can activate dendritic cells[30], T cells[31],[32], and myeloid cells[33], we speculate that its high systemic levels directly prime these immune cells at distant sites( e. g., the lung) to mount an intense allergic inflammation in response to a second stimulatory signal( e. g., allergens in the lung airways); however, the specific contribution of these immune cells to the atopic march downstream of TSLP-mediated activation remains a subject for future investigation. Of note, elevated TSLP expression is also reported in psoriatic skin[34]; however, there is no evidence linking psoriasis to predisposition to asthma. This phenomenon could be explained by the dominance of Th1 response in patients with psoriasis and the unresponsiveness of their immune cells to TSLP[34]. The findings outlined in this report have a potentially important implication for human health. They provide a plausible explanation of why a large number of AD patients develop asthma and other allergic disorders later in life[35],[36]. Because TSLP overproduction is triggered by skin-barrier defects and faithfully mirrors the severity of these defects[15], our data emphasize that an early and aggressive treatment of the underlying skin-barrier defects in AD-prone patients[10],[11] may be more beneficial in preventing asthma than treating the outbreaks of AD lesions[6]. Although serum TSLP levels in AD patients are yet to be determined, high TSLP expression levels in human AD lesions[37] suggest that this diffusible cytokine could also reach systemic levels sufficient to trigger atopic march in AD patients. If indeed serum TSLP levels are elevated in AD patients, our findings suggest that an aggressive management of TSLP levels in these patients will lower the incidence of asthma later in their lives.
Eczema ( atopic dermatitis ) is a common allergic skin inflammation that has a particularly high prevalence among children . Importantly , a large proportion of people suffering from eczema go on to develop asthma later in life . Although the susceptibility of eczema patients to asthma is well documented , the mechanism that mediates “atopic march”—the progression from eczema to asthma—is unclear . We used genetic engineering to generate mice with chronic skin-barrier defects and a subsequent eczema-like disorder . With these mice , we were able to investigate how skin-specific defects predisposed the lungs to allergic asthma . We identified thymic stromal lymphopoietin ( TSLP ) , a cytokine that is secreted by barrier-defective skin into the systemic circulation , as the agent sensitizing the lung to allergens . We demonstrated that high systemic levels of skin-derived TSLP were both required and sufficient to render lung airways hypersensitive to allergens . Thus , these data suggest that early treatment of skin-barrier defects to prevent TSLP overexpression , and systemic inhibition of TSLP , may be crucial in preventing the progression from eczema to asthma .