title: Distinct roles of the anaphylatoxins C3a and C5a in dendritic cell-mediated allergic asthma.
abstract: Conventional dendritic cells (cDC) are necessary and sufficient to drive mixed maladaptive Th2/Th17 immune responses toward aeroallergens in experimental allergy models. Previous studies suggest that the anaphylatoxin C3a promotes, whereas C5a protects from the development of maladaptive immunity during allergen sensitization. However, only limited evidence exists that such effects are directly mediated through anaphylatoxin-receptor signaling in cDCs. In this study, we assessed the impact of C3a and C5a on cDC-mediated induction pulmonary allergy by adoptively transferring house dust mite (HDM)-pulsed bone marrow-derived DCs (BMDC) from wild-type (WT) C3aR(-/-), C5aR1(-/-), or C3aR(-/-)/C5aR1(-/-) into WT mice. Transfer of HDM-pulsed WT BMDCs promoted a strong asthmatic phenotype characterized by marked airway resistance, strong Th2 cytokine, and mucus production, as well as mixed eosinophilic and neurophilic airway inflammation. Surprisingly, C3aR(-/-) cDCs induced a strong allergic phenotype, but no IL-17A production, whereas HDM-pulsed C5aR1(-/-) cDCs failed to drive pulmonary allergy. Transfer of C3aR(-/-)/C5aR1(-/-) cDCs resulted in a slightly reduced allergic phenotype associated with increased IFN-γ production. Mechanistically, C3aR and C5aR1 signaling is required for IL-23 production from HDM-pulsed BMDCs in vitro. Furthermore, C3aR(-/-) BMDCs produced less IL-1β. The mechanisms underlying the failure of C5aR1(-/-) BMDCs to induce experimental allergy include a reduced capability to migrate into the lung tissue and a decreased potency to direct pulmonary homing of effector T cells. Thus, we uncovered a crucial role for C5a, but only a minor role for C3a in BMDC-mediated pulmonary allergy, suggesting that BMDCs inappropriately reflect the impact of complement on lung cDC-mediated allergic asthma development.
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck and Airway Research Center North, member of the German Center for Lung Research, 23538 Lübeck, Germany;
authors.forename: Carsten
authors.initials: C
authors.lastname: Engelke
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck and Airway Research Center North, member of the German Center for Lung Research, 23538 Lübeck, Germany;
authors.forename: Anna V
authors.initials: AV
authors.lastname: Wiese
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck and Airway Research Center North, member of the German Center for Lung Research, 23538 Lübeck, Germany;
authors.forename: Inken
authors.initials: I
authors.lastname: Schmudde
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck and Airway Research Center North, member of the German Center for Lung Research, 23538 Lübeck, Germany;
authors.forename: Fanny
authors.initials: F
authors.lastname: Ender
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck and Airway Research Center North, member of the German Center for Lung Research, 23538 Lübeck, Germany;
authors.forename: Heike A
authors.initials: HA
authors.lastname: Ströver
authors.affiliation: Cell Analysis Core, University of Lübeck, 23538 Lübeck, Germany;
authors.forename: Tillmann
authors.initials: T
authors.lastname: Vollbrandt
authors.affiliation: Institute for Anatomy, University of Lübeck and Airway Research Center North, member of the German Center for Lung Research, 23538 Lübeck, Germany; and.
authors.forename: Peter
authors.initials: P
authors.lastname: König
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck and Airway Research Center North, member of the German Center for Lung Research, 23538 Lübeck, Germany; yves.laumonnier@uksh.de joerg.koehl@uksh.de.
authors.forename: Yves
authors.initials: Y
authors.lastname: Laumonnier
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck and Airway Research Center North, member of the German Center for Lung Research, 23538 Lübeck, Germany; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229 yves.laumonnier@uksh.de joerg.koehl@uksh.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology; D001249:Asthma / Q000276:immunology*; D002478:Cells, Cultured; D015926:Complement C3a / Q000378:metabolism*; D015936:Complement C5a / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D039981:Pyroglyphidae; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics; D011951:Receptors, Complement / Q000235:genetics; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D039741:Antigens, Dermatophagoides; C000591759:C5ar1 protein, mouse; D016207:Cytokines; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; C085567:complement C3a receptor; D015926:Complement C3a; D015936:Complement C5a