title: Complement component 3C3 and C3a receptor are required in chitin-dependent allergic sensitization to Aspergillus fumigatus but dispensable in chitin-induced innate allergic inflammation.
abstract: Levels of the anaphylatoxin C3a are increased in patients with asthma compared with those in nonasthmatics and increase further still during asthma exacerbations. However, the role of C3a during sensitization to allergen is poorly understood. Sensitization to fungal allergens, such as Aspergillus fumigatus, is a strong risk factor for the development of asthma. Exposure to chitin, a structural polysaccharide of the fungal cell wall, induces innate allergic inflammation and may promote sensitization to fungal allergens. Here, we found that coincubation of chitin with serum or intratracheal administration of chitin in mice resulted in the generation of C3a. We established a model of chitin-dependent sensitization to soluble Aspergillus antigens to test the contribution of complement to these events. C3(-/-) and C3aR(-/-) mice were protected from chitin-dependent sensitization to Aspergillus and had reduced lung eosinophilia and type 2 cytokines and serum IgE. In contrast, complement-deficient mice were not protected against chitin-induced innate allergic inflammation. In sensitized mice, plasmacytoid dendritic cells from complement-deficient animals acquired a tolerogenic profile associated with enhanced regulatory T cell responses and suppressed Th2 and Th17 responses specific for Aspergillus. Thus, chitin induces the generation of C3a in the lung, and chitin-dependent allergic sensitization to Aspergillus requires C3aR signaling, which suppresses regulatory dendritic cells and T cells and induces allergy-promoting T cells.
authors.affiliation: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: René M
authors.initials: RM
authors.lastname: Roy
authors.forename: Hugo C
authors.initials: HC
authors.lastname: Paes
authors.forename: Som G
authors.initials: SG
authors.lastname: Nanjappa
authors.forename: Ron
authors.initials: R
authors.lastname: Sorkness
authors.forename: David
authors.initials: D
authors.lastname: Gasper
authors.forename: Alana
authors.initials: A
authors.lastname: Sterkel
authors.forename: Marcel
authors.initials: M
authors.lastname: Wüthrich
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Klein
mesh_terms: D000818:Animals; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000276:immunology / Q000473:pathology; D001232:Aspergillus fumigatus / Q000276:immunology*; D002686:Chitin / Q000276:immunology*; D003176:Complement C3 / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011951:Receptors, Complement / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D003176:Complement C3; D011951:Receptors, Complement; C085567:complement C3a receptor; D002686:Chitin
references.citation: J Allergy Clin Immunol. 1987 Jul;80(1):24-32
references.pmid: 3496373
references.citation: J Exp Med. 2004 Jul 5;200(1):89-98
references.pmid: 15238608
references.citation: Nature. 2009 Jan 29;457(7229):585-8
references.pmid: 19060881
references.citation: Am J Respir Crit Care Med. 2010 Dec 1;182(11):1362-8
references.pmid: 20639442
references.citation: J Immunol. 2001 Feb 1;166(3):2025-32
references.pmid: 11160252
references.citation: Nat Protoc. 2008;3(6):1101-8
references.pmid: 18546601
references.citation: Expert Rev Clin Immunol. 2010 Mar;6(2):269-77
references.pmid: 20402389
references.citation: Biol Pharm Bull. 1998 Feb;21(2):129-32
references.pmid: 9514606
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5360-5
references.pmid: 21402950
references.citation: mBio. 2011 Aug 30;2(5):
references.pmid: 21878570
references.citation: J Allergy Clin Immunol. 2003 Sep;112(3):525-30
references.pmid: 13679811
references.citation: Nat Immunol. 2010 Oct;11(10):928-35
references.pmid: 20802484
references.citation: Immunology. 1999 May;97(1):166-72
references.pmid: 10447728
references.citation: J Immunol. 1999 Jan 15;162(2):1127-36
references.pmid: 9916743
references.citation: Methods Mol Biol. 2000;132:365-86
references.pmid: 10547847
references.citation: Mol Immunol. 2004 Jun;41(2-3):123-31
references.pmid: 15159057
references.citation: J Immunol. 2012 Sep 1;189(5):2545-52
references.pmid: 22851704
references.citation: Am J Respir Crit Care Med. 2004 Mar 15;169(6):726-32
references.pmid: 14701711
references.citation: Fungal Genet Biol. 2006 May;43(5):366-75
references.pmid: 16531086
references.citation: J Immunol. 2010 Nov 1;185(9):5628-36
references.pmid: 20870944
references.citation: Mycoses. 2010 Mar 1;53(2):138-43
references.pmid: 19207831
references.citation: Eur Respir J. 2000 Dec;16(6):1095-101
references.pmid: 11292112
references.citation: J Exp Med. 2010 Dec 20;207(13):2907-19
references.pmid: 21149550
references.citation: Nat Med. 2009 Apr;15(4):410-6
references.pmid: 19330007
references.citation: J Immunol. 2011 Sep 1;187(5):2261-7
references.pmid: 21824866
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):11086-91
references.pmid: 16829581
references.citation: Blood. 2008 Dec 15;112(13):5084-94
references.pmid: 18812470
references.citation: Eur J Immunol. 2005 Apr;35(4):1086-96
references.pmid: 15756642
references.citation: J Allergy Clin Immunol. 2007 Aug;120(2):334-42
references.pmid: 17544098
references.citation: Nature. 2007 May 3;447(7140):92-6
references.pmid: 17450126
references.citation: J Allergy Clin Immunol. 2010 May;125(5):1028-1036.e13
references.pmid: 20398920
references.citation: J Immunol. 2001 Oct 15;167(8):4141-5
references.pmid: 11591733
references.citation: J Exp Med. 2005 Mar 21;201(6):981-91
references.pmid: 15781587
references.citation: J Vis Exp. 2011 May 02;(51):
references.pmid: 21587154
references.citation: N Engl J Med. 2007 Nov 15;357(20):2082-4
references.pmid: 18003965
references.citation: J Immunol. 2009 Apr 15;182(8):5123-30
references.pmid: 19342693
references.citation: Am J Respir Crit Care Med. 2010 Dec 15;182(12):1482-91
references.pmid: 20656945
references.citation: Am J Respir Cell Mol Biol. 2002 Oct;27(4):413-8
references.pmid: 12356574
references.citation: J Exp Med. 1991 Jun 1;173(6):1345-56
references.pmid: 2033368
references.citation: J Immunol. 2009 Dec 15;183(12):8044-53
references.pmid: 19933856
references.citation: J Exp Med. 1998 Jul 20;188(2):373-86
references.pmid: 9670049
references.citation: Immunity. 2006 Oct;25(4):665-75
references.pmid: 17027299
references.citation: J Immunol. 2002 Nov 15;169(10):5926-33
references.pmid: 12421977
references.citation: Am J Transplant. 2005 Aug;5(8):1808-19
references.pmid: 15996227
references.citation: J Immunol. 2013 Apr 1;190(7):3480-92
references.pmid: 23420883
references.citation: J Immunol. 2006 Feb 15;176(4):2161-72
references.pmid: 16455972
references.citation: J Immunol. 2008 Sep 15;181(6):4279-86
references.pmid: 18768886
references.citation: Hum Genet. 2004 Sep;115(4):295-301
references.pmid: 15278436
references.citation: J Clin Invest. 2004 Aug;114(3):399-407
references.pmid: 15286806
references.citation: Exp Dermatol. 2012 Jan;21(1):52-6
references.pmid: 22151392
references.citation: Nat Med. 2002 Sep;8(9):1024-32
references.pmid: 12145647
references.citation: Infect Immun. 2010 Aug;78(8):3585-94
references.pmid: 20498262
references.citation: Annu Rev Immunol. 1998;16:545-68
references.pmid: 9597141
references.citation: Respir Res. 2004 Sep 15;5:12
references.pmid: 15377395
references.citation: J Immunol. 2002 Nov 15;169(10):5904-11
references.pmid: 12421974