title: IL-33-dependent induction of allergic lung inflammation by FcγRIII signaling.
abstract: Atopic asthma is a chronic inflammatory disease of the lungs generally marked by excessive Th2 inflammation. The role of allergen-specific IgG in asthma is still controversial; however, a receptor of IgG-immune complexes (IgG-ICs), FcγRIII, has been shown to promote Th2 responses through an unknown mechanism. Herein, we demonstrate that allergen-specific IgG-ICs, formed upon reexposure to allergen, promoted Th2 responses in two different models of IC-mediated inflammation that were independent of a preformed T cell memory response. Development of Th2-type airway inflammation was shown to be both FcγRIII and TLR4 dependent, and T cells were necessary and sufficient for this process to occur, even in the absence of type 2 innate lymphoid cells. We sought to identify downstream targets of FcγRIII signaling that could contribute to this process and demonstrated that bone marrow-derived DCs, alveolar macrophages, and respiratory DCs significantly upregulated IL-33 when activated through FcγRIII and TLR4. Importantly, IC-induced Th2 inflammation was dependent on the ST2/IL-33 pathway. Our results suggest that allergen-specific IgG can enhance secondary responses by ligating FcγRIII on antigen-presenting cells to augment development of Th2-mediated responses in the lungs via an IL-33-dependent mechanism.
authors.affiliation: Committee on Immunology, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Melissa Y
authors.initials: MY
authors.lastname: Tjota
authors.forename: Jesse W
authors.initials: JW
authors.lastname: Williams
authors.forename: Tiffany
authors.initials: T
authors.lastname: Lu
authors.forename: Bryan S
authors.initials: BS
authors.lastname: Clay
authors.forename: Tiara
authors.initials: T
authors.lastname: Byrd
authors.forename: Cara L
authors.initials: CL
authors.lastname: Hrusch
authors.forename: Donna C
authors.initials: DC
authors.lastname: Decker
authors.forename: Claudia Alves
authors.initials: CA
authors.lastname: de Araujo
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Bryce
authors.forename: Anne I
authors.initials: AI
authors.lastname: Sperling
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D003713:Dendritic Cells / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006967:Hypersensitivity; D006969:Hypersensitivity, Immediate / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008168:Lung / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction; D018418:Th2 Cells
chemical_list: C506535:Il33 protein, mouse; D007074:Immunoglobulin G; D000067596:Interleukin-33; D007378:Interleukins; D017452:Receptors, IgG