title: Immune complexes inhibit IL-1 secretion and inflammasome activation.
abstract: IgG immune complexes have been shown to modify immune responses driven by APCs in either a pro- or anti-inflammatory direction depending upon the context of stimulation. However, the ability of immune complexes to modulate the inflammasome-dependent innate immune response is unknown. In this study, we show that IgG immune complexes suppress IL-1α and IL-1β secretion through inhibition of inflammasome activation. The mechanism by which this inhibition occurs is via immune complex ligation of activating FcγRs, resulting in prevention of both activation and assembly of the inflammasome complex in response to nucleotide-binding domain leucine-rich repeat (NLR) P3, NLRC4, or AIM2 agonists. In vivo, administration of Ag in the form of an immune complex during priming of the immune response inhibited resultant adaptive immune responses in an NLRP3-dependent model of allergic airway disease. Our data reveal an unexpected mechanism regulating CD4(+) T cell differentiation, by which immune complexes suppress inflammasome activation and the generation of IL-1α and IL-1β from APCs, which are critical for the Ag-driven differentiation of CD4(+) T cells.
authors.affiliation: Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Inflammation Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: John R
authors.initials: JR
authors.lastname: Janczy
authors.affiliation: Inflammation Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Ceren
authors.initials: C
authors.lastname: Ciraci
authors.affiliation: Inflammation Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Stefanie
authors.initials: S
authors.lastname: Haasken
authors.affiliation: Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan;
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Olivier
authors.affiliation: Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Inflammation Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242; and.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Cassel
authors.affiliation: Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Inflammation Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242; and Veterans Affairs Medical Center, Iowa City, IA 52241 fayyaz-sutterwala@uiowa.edu.
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000534:Alum Compounds / Q000008:administration & dosage; D000818:Animals; D000936:Antigen-Antibody Complex / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology*; D053582:Interleukin-1alpha / Q000096:biosynthesis / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000378:metabolism*; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000936:Antigen-Antibody Complex; D058847:Inflammasomes; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D017452:Receptors, IgG; C041524:aluminum sulfate; D010047:Ovalbumin