title: Signaling through FcRγ-associated receptors on dendritic cells drives IL-33-dependent TH2-type responses.
abstract: BACKGROUND
  Although allergic sensitization can be generated against various allergens, it is unknown how such a diversity of antigens is able to promote TH2-mediated inflammation leading to atopy. Our previous studies demonstrated that allergen-specific IgG immune complexes (ICs) and house dust mite (HDM) extract both induced dendritic cells (DCs) to drive TH2-mediated inflammation, but the mechanism by which these diverse stimuli produce similar responses is unknown.
  
  
  OBJECTIVE
  We sought to identify the DC signaling pathways used by TH2 stimuli to promote TH2-mediated inflammation.
  
  
  METHODS
  C57BL/6, FcγRIII(-/-), FcRγ(-/-), and ST2(-/-) mice were sensitized and challenged with HDM, and inflammation was assessed based on results of flow cytometry and histology and cytokine production. Bone marrow-derived DCs from these strains were used in signaling and adoptive transfer experiments.
  
  
  RESULTS
  Our findings indicate that 2 distinct TH2 stimuli, ICs and HDM, use the FcRγ-associated receptors FcγRIII and Dectin-2, respectively, to promote TH2-mediated lung inflammation. In this study we demonstrate that both ICs and HDM induce expression of IL-33, a critical mediator in asthma pathogenesis and the differentiation of TH2 cells, in DCs. Upregulation of IL-33 in DCs is dependent on FcRγ, Toll-like receptor 4, and phosphoinositide 3-kinase. Exogenous IL-33 is sufficient to restore the development of TH2 responses in FcRγ-deficient mice. Finally, adoptive transfer of allergen-pulsed FcRγ(+/-) bone-marrow derived DCs restores the development of TH2-type inflammation in FcRγ-deficient mice, demonstrating the necessity of this signaling pathway in DCs for allergen-induced inflammation.
  
  
  CONCLUSIONS
  These data identify a mechanism whereby TH2 stimuli signal through FcRγ-associated receptors on DCs to upregulate IL-33 production and induce TH2-mediated allergic airway inflammation.
authors.affiliation: Committee on Immunology, University of Chicago, Chicago, Ill; Medical Scientist Training Program, University of Chicago, Chicago, Ill.
authors.forename: Melissa Y
authors.initials: MY
authors.lastname: Tjota
authors.affiliation: Department of Medicine, Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Ill.
authors.forename: Cara L
authors.initials: CL
authors.lastname: Hrusch
authors.affiliation: Department of Medicine, Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Ill.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Blaine
authors.affiliation: Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, Chicago, Ill.
authors.forename: Jesse W
authors.initials: JW
authors.lastname: Williams
authors.affiliation: Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Harvard Medical School, Boston, Mass.
authors.forename: Nora A
authors.initials: NA
authors.lastname: Barrett
authors.affiliation: Committee on Immunology, University of Chicago, Chicago, Ill; Department of Medicine, Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Ill; Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, Chicago, Ill. Electronic address: asperlin@uchicago.edu.
authors.forename: Anne I
authors.initials: AI
authors.lastname: Sperling
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D039741:Antigens, Dermatophagoides / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology; D037181:Lectins, C-Type / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000235:genetics; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000936:Antigen-Antibody Complex; D039741:Antigens, Dermatophagoides; D016207:Cytokines; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D037181:Lectins, C-Type; D017452:Receptors, IgG; D018123:Receptors, Interleukin; C445340:dectin-2, mouse
keywords: Dendritic cells; FcRγ; T(H)2; allergic airway inflammation; house dust mite; immune complexes; lungs
references.citation: J Immunol. 2009 Jan 15;182(2):1119-28
references.pmid: 19124755
references.citation: J Dermatol Sci. 2007 Feb;45(2):77-86
references.pmid: 17046204
references.citation: Nat Med. 2012 May 04;18(5):673-83
references.pmid: 22561831
references.citation: Clin Exp Immunol. 2009 Oct;158(1):10-9
references.pmid: 19737225
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20459-64
references.pmid: 21059925
references.citation: J Immunol. 2009 Oct 15;183(8):5094-103
references.pmid: 19801525
references.citation: J Exp Med. 2000 Mar 20;191(6):1069-76
references.pmid: 10727469
references.citation: Inflamm Res. 2012 Jun;61(6):547-50
references.pmid: 22349136
references.citation: Trends Mol Med. 2011 Oct;17(10):604-11
references.pmid: 21741880
references.citation: J Asthma. 2013 Oct;50(8):803-9
references.pmid: 23855553
references.citation: Immunol Allergy Clin North Am. 2005 Feb;25(1):1-14
references.pmid: 15579361
references.citation: J Clin Invest. 2013 May;123(5):2287-97
references.pmid: 23585480
references.citation: J Biol Chem. 2006 Dec 15;281(50):38854-66
references.pmid: 17050534
references.citation: J Exp Med. 2007 Aug 6;204(8):1875-89
references.pmid: 17664287
references.citation: J Exp Med. 2008 Jan 21;205(1):13-7
references.pmid: 18195077
references.citation: J Leukoc Biol. 2009 Jun;85(6):966-77
references.pmid: 19289601
references.citation: J Allergy Clin Immunol. 2010 Jan;125(1):247-56.e1-8
references.pmid: 20109752
references.citation: J Investig Allergol Clin Immunol. 2000 Jan-Feb;10(1):24-9
references.pmid: 10780796
references.citation: Clin Exp Allergy. 1998 Oct;28(10):1258-63
references.pmid: 9824393
references.citation: J Exp Med. 2011 Mar 14;208(3):593-604
references.pmid: 21357742
references.citation: J Immunol Methods. 1999 Feb 1;223(1):77-92
references.pmid: 10037236
references.citation: J Immunol. 2007 Jan 1;178(1):480-8
references.pmid: 17182587
references.citation: Annu Rev Pharmacol Toxicol. 2002;42:81-98
references.pmid: 11807165
references.citation: Nat Med. 2012 May 04;18(5):716-25
references.pmid: 22561835
references.citation: J Immunol. 2011 Jul 1;187(1):164-71
references.pmid: 21622859
references.citation: J Immunol. 2014 Feb 15;192(4):1361-71
references.pmid: 24453247
references.citation: J Allergy Clin Immunol. 1984 Feb;73(2):276-82
references.pmid: 6699311
references.citation: J Allergy Clin Immunol. 2013 Mar;131(3):856-65
references.pmid: 23380221
references.citation: Immunol Rev. 2011 Jul;242(1):51-68
references.pmid: 21682738
references.citation: J Allergy (Cairo). 2012;2012:236075
references.pmid: 23150737
references.citation: Immunol Rev. 2009 Nov;232(1):42-58
references.pmid: 19909355
references.citation: Nat Immunol. 2010 Aug;11(8):647-55
references.pmid: 20644570
references.citation: J Immunol. 2012 Oct 1;189(7):3421-9
references.pmid: 22922818
references.citation: PLoS Pathog. 2009 Jun;5(6):e1000464
references.pmid: 19503602
references.citation: J Allergy Clin Immunol. 2013 Sep;132(3):676-685.e13
references.pmid: 23759184
references.citation: Immunity. 2010 May 28;32(5):681-91
references.pmid: 20493731
references.citation: Nat Commun. 2013;4:2990
references.pmid: 24356538
references.citation: J Immunol. 2000 Apr 1;164(7):3878-86
references.pmid: 10725750
references.citation: J Exp Med. 2009 Aug 31;206(9):2037-51
references.pmid: 19703985