64 Effect of Formoterol on Eosinophil Trans-Basement Migration Induced by Interleukin-8-Stimulated Neutrophils

62 Keratinocytic Thymic Stromal Lymphopoietin Plays an Important Role in Epicutaneous Sensitization and the Atopic March Juan Manuel Leyva Castillo, MSc, Pierre Hener, Hua Jiang, PhD, Daniel Metzger, PhD, Pierre Chambon, PhD, and Mei Li, PhD. Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR-7104/INSERM U964/UdS, Illkirch CEDEX, France. Background: Atopic dermatitis (AD or eczema) often precedes the development of asthma and allergic rhinitis in atopic subjects, a phenomenon known as atopic march. An important role of epicutaneous (e.c.) sensitization has been recognized in the atopic march; however, the factors involved in e.c. sensitization remain poorly understood. Our previous studies using mouse models have shown that induced overexpression of Thymic Stromal Lymphopoietin (TSLP) in keratinocytes not only triggers an AD [Li, M. et al. Proc Natl Acad Sci U S A. 2006;103:11736–11741] but also aggravates experimental asthma induced by systemic sensitization and airway challenge of ovalbumin (OVA) [Zhang Z, et al. Proc Natl Acad Sci U S A. 2009;106:1536–1541], suggesting that TSLP represents an important factor linking AD to asthma. However, whether keratinocytic TSLP is essentially required for developing e.c. sensitization and triggering the atopic march remained to be determined. Methods: We develop a mouse model in which e.c. sensitization of OVA through tape-stripped skin is followed by intranasal challenge to induce an allergic asthma. TSLPep2/2mice (in which TSLP is selectively ablated in epidermal keratinocytes at adult stage) or TSLPover mice (in which keratinocytic TSLP overexpression is induced by topical application of MC903, a low-calcemic vitamin D analog) are subjected to this mouse model. Results: Upon OVA e.c. treatment, TSLPep2/2 mice develop a defective allergen sensitization evidenced by decreased production of OVA-specific IgE and IgG1 and a reduction of the secretion of Th2 and Th17 (but not Th1) cytokines by in vitro OVA stimulated splenocytes. TSLPep2/2 mice also exhibit a decreased OVA-induced skin inflammation. Finally, upon intranasal challenge, TSLPep2/2 mice develop a less severe airway allergic inflammation and a reduced airway hyperresponsiveness. In contrast, overproduction of keratinocytic TSLP boosts the e.c. sensitization and triggers an aggravated asthma. Conclusions: Our results demonstrate an important role of keratinocytic TSLP in developing epicutaneous sensitization, generating allergic skin inflammation and triggering the atopic march. Thus, blocking the expression or activity of keratinocytic TSLP could be helpful to limit epicutaneous sensitization and prevent the atopic march. This study is supported by CNRS, INSERM, ARI and ANR projects (07PHYSIO-002–01 and JCJC-1106-01).