title: Thymic stromal lymphopoietin plays divergent roles in murine models of atopic and nonatopic airway inflammation.
abstract: BACKGROUND
  Thymic stromal lymphopoietin (TSLP) is a cytokine primarily produced by epithelial cells, which has been shown to be a potent inducer of T-helper 2 (Th2)-type responses. However, TSLP has pleiotropic effects upon immune cells, and although extensively studied in the context of atopic asthma, its relevance as a therapeutic target and its role in the pathogenesis of nonatopic asthma remains unknown. We sought to investigate the role of TSLP in atopic, nonatopic and viral-induced exacerbations of pulmonary inflammation.
  
  
  METHODS
  Using stringently defined murine models of atopic, nonatopic and virally exacerbated forms of pulmonary inflammation, we compared inflammatory responses of C57BL/6 wild-type (WT) and TSLP receptor-deficient (TSLPR KO) mice.
  
  
  RESULTS
  Thymic stromal lymphopoietin receptor (TSLPR) signaling was crucial for the development of atopic asthma. Specifically, TSLPR signaling to lung recruited CD4+ T cells enhanced eosinophilia, goblet cell hyperplasia, and overall inflammation within the airways. In contrast, the absence of TSLPR signaling was associated with strikingly exaggerated pulmonary neutrophilic inflammation in a nonatopic model of airway inflammation. The inflammation was associated with excessive levels of interleukin (IL)-17A in the lungs, indicating that TSLP negatively regulates IL-17A. In addition, in a model of influenza-induced exacerbation of atopic airway inflammation, the absence of TSLPR signaling also led to exaggerated neutrophilic inflammation.
  
  
  CONCLUSIONS
  Thymic stromal lymphopoietin plays divergent roles in the pathogenesis of atopic and nonatopic asthma phenotypes by either enhancing Th2 responses or curtailing T-helper 17 responses. These findings raise important caveats for the design of therapeutic interventions targeting TSLP in asthma.
authors: Service de Pneumologie, Faculty of Biology and Medicine, University of Lausanne, CHUV, Lausanne, Switzerland.
authors: K
authors: K
authors: Yadava
authors: J
authors: J
authors: Massacand
authors: I
authors: I
authors: Mosconi
authors: L P
authors: LP
authors: Nicod
authors: N L
authors: NL
authors: Harris
authors: B J
authors: BJ
authors: Marsland
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001249:Asthma / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000276:immunology*; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse
keywords: IL-17A; atopic airway inflammation; nonatopic airway inflammation; thymic stromal lymphopoietin