title: CCL17 production by dendritic cells is required for NOD1-mediated exacerbation of allergic asthma.
abstract: BACKGROUND
  Pattern recognition receptors are attractive targets for vaccine adjuvants, and polymorphisms of the innate receptor NOD1 have been associated with allergic asthma.
  
  
  OBJECTIVE
  To elucidate whether NOD1 agonist may favor allergic asthma in humans through activation of dendritic cells, and to evaluate the mechanisms involved using an in vivo model.
  
  
  METHODS
  NOD1-primed dendritic cells from allergic and nonallergic donors were characterized in vitro on their phenotype, cytokine secretion, and Th2 polarizing ability. The in vivo relevance was examined in experimental allergic asthma, and the mechanisms were assessed using transfer of NOD1-conditioned dendritic cells from wild-type or CCL17-deficient mice.
  
  
  RESULTS
  NOD1 priming of human dendritic cells promoted a Th2 polarization profile that involved the production of CCL17 and CCL22 in nonallergic subjects but only CCL17 in allergic patients, without requiring allergen costimulation. Moreover, NOD1-primed dendritic cells from allergic donors exhibited enhanced maturation that led to abnormal CCL22 and IL-10 secretion compared with nonallergic donors. In mice, systemic NOD1 ligation exacerbated allergen-induced experimental asthma by amplifying CCL17-mediated Th2 responses in the lung. NOD1-mediated sensitization of purified murine dendritic cells enhanced production of CCL17 and CCL22, but not of thymic stromal lymphopoietin and IL-33, in vitro. Consistently, adoptive transfer of NOD1-conditioned dendritic cells exacerbated the Th2 pulmonary response in a CCL17-dependent manner in vivo.
  
  
  CONCLUSIONS
  Data from this study unveil a deleterious role of NOD1 in allergic asthma through direct induction of CCL17 by dendritic cells, arguing for a need to address vaccine formulation safety issues related to allergy.
authors.affiliation: 1 Pulmonary Immunity, Institut National de la Santé et de la Recherche Médicale, Lille, France.
authors.forename: Saliha
authors.initials: S
authors.lastname: Ait Yahia
authors.forename: Imane
authors.initials: I
authors.lastname: Azzaoui
authors.forename: Laetitia
authors.initials: L
authors.lastname: Everaere
authors.forename: Han
authors.initials: H
authors.lastname: Vorng
authors.forename: Cécile
authors.initials: C
authors.lastname: Chenivesse
authors.forename: Philippe
authors.initials: P
authors.lastname: Marquillies
authors.forename: Catherine
authors.initials: C
authors.lastname: Duez
authors.forename: Myriam
authors.initials: M
authors.lastname: Delacre
authors.forename: Teddy
authors.initials: T
authors.lastname: Grandjean
authors.forename: Joanne
authors.initials: J
authors.lastname: Balsamelli
authors.forename: Martine
authors.initials: M
authors.lastname: Fanton d'Andon
authors.forename: Ying
authors.initials: Y
authors.lastname: Fan
authors.forename: Coline
authors.initials: C
authors.lastname: Ple
authors.forename: Catherine
authors.initials: C
authors.lastname: Werts
authors.forename: Ivo Gomperts
authors.initials: IG
authors.lastname: Boneca
authors.forename: Benoit
authors.initials: B
authors.lastname: Wallaert
authors.forename: Mathias
authors.initials: M
authors.lastname: Chamaillard
authors.forename: Anne
authors.initials: A
authors.lastname: Tsicopoulos
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D054414:Chemokine CCL17 / Q000276:immunology*; D054422:Chemokine CCL22 / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D053474:Nod1 Signaling Adaptor Protein / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D010641:Phenotype; D011110:Polymorphism, Genetic; D018418:Th2 Cells / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000485:Allergens; D054414:Chemokine CCL17; D054422:Chemokine CCL22; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D016753:Interleukin-10