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PMID: 16511606 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

A regulatory role for the C5a anaphylatoxin in type 2 immunity in asthma.

The Journal of clinical investigation ·Vol. 116 ·No. 3 ·2006-03-00 ·Pages 783-96

Köhl J, Baelder R, Lewkowich IP, Pandey MK, Hawlisch H, Wang L, Best J, Herman NS, Sproles AA, Zwirner J, Whitsett JA, Gerard C, Sfyroera G, Lambris JD, Wills-Karp M

Abstract

Complement component 5 (C5) has been described as either promoting or protecting against airway hyperresponsiveness (AHR) in experimental allergic asthma, suggesting pleomorphic effects of C5. Here we report that local pharmacological targeting of the C5a receptor (C5aR) prior to initial allergen sensitization in murine models of inhalation tolerance or allergic asthma resulted in either induction or marked enhancement of Th2-polarized immune responses, airway inflammation, and AHR. Importantly, C5aR-deficient mice exhibited a similar, increased allergic phenotype. Pulmonary allergen exposure in C5aR-targeted mice resulted in increased sensitization and accumulation of CD4+ CD69+ T cells associated with a marked increase in pulmonary myeloid, but not plasmacytoid, DC numbers. Pulmonary DCs from C5aR-targeted mice produced large amounts of CC chemokine ligand 17 (CCL17) and CCL22 ex vivo, suggesting a negative impact of C5aR signaling on pulmonary homing of Th2 cells. In contrast, C5aR targeting in sensitized mice led to suppressed airway inflammation and AHR but was still associated with enhanced production of Th2 effector cytokines. These data suggest a dual role for C5a in allergic asthma, i.e., protection from the development of maladaptive type 2 immune responses during allergen sensitization at the DC/T cell interface but enhancement of airway inflammation and AHR in an established inflammatory environment.

MeSH Terms
Allergens/administration & dosage,immunology Animals Asthma/genetics,immunology Bronchi/immunology,metabolism Bronchial Hyperreactivity/genetics,immunology Dendritic Cells/immunology Disease Models, Animal Immunity, Innate/genetics Inflammation Mediators/antagonists & inhibitors,physiology Lung/cytology,immunology,metabolism Mice Mice, Inbred BALB C Mice, Transgenic Mucus/metabolism Ovalbumin/administration & dosage,immunology Receptor, Anaphylatoxin C5a/antagonists & inhibitors,physiology Signal Transduction/genetics,immunology Th2 Cells/immunology,metabolism
Chemicals
Allergens Inflammation Mediators Receptor, Anaphylatoxin C5a Ovalbumin
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Köhl Jörg
Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA. [email protected]
Baelder Ralf
Lewkowich Ian P
Pandey Manoj K
Hawlisch Heiko
Wang Lihua
Best Jennifer
Herman Nancy S
Sproles Alyssa A
Zwirner Jörg
Whitsett Jeffrey A
Gerard Craig
Sfyroera Georgia
Lambris John D
Wills-Karp Marsha
References (62)
62 references, click to expand
  1. Cutting edge: differential chemokine production by myeloid and plasmacytoid dendritic cells.
    J Immunol. 2002 Dec 15;169(12):6673-6 PMID: 12471096
  2. In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma.
    J Exp Med. 2005 Mar 21;201(6):981-91 PMID: 15781587
  3. Differences in circulating dendritic cell subtypes in cord blood and peripheral blood of healthy and allergic children.
    Clin Exp Allergy. 2003 May;33(5):633-9 PMID: 12752592
  4. Influenza virus-induced dendritic cell maturation is associated with the induction of strong T cell immunity to a coadministered, normally nonimmunogenic protein.
    J Exp Med. 2003 Jul 7;198(1):133-44 PMID: 12847140
  5. Characterization of C5aR expression on murine myeloid and lymphoid cells by the use of a novel monoclonal antibody.
    Immunol Lett. 2003 Jul 3;88(1):47-52 PMID: 12853161
  6. Chemokines in allergic airway disease.
    Curr Opin Pharmacol. 2003 Aug;3(4):443-8 PMID: 12901955
  7. Taking our breath away: dendritic cells in the pathogenesis of asthma.
    Nat Rev Immunol. 2003 Dec;3(12):994-1003 PMID: 14647481
  8. C5a mutants are potent antagonists of the C5a receptor (CD88) and of C5L2: position 69 is the locus that determines agonism or antagonism.
    J Biol Chem. 2004 Jan 2;279(1):142-51 PMID: 14570896
  9. Influenza and asthma: adding to the respiratory burden.
    Nat Immunol. 2004 Mar;5(3):243-4 PMID: 14985710
  10. Allergy to house dust mites and asthma.
    P R Health Sci J. 2004 Mar;23(1):47-57 PMID: 15125219
  11. Time to draw breath: asthma-susceptibility genes are identified.
    Nat Rev Genet. 2004 May;5(5):376-87 PMID: 15143320
  12. The anaphylatoxins bridge innate and adaptive immune responses in allergic asthma.
    Mol Immunol. 2004 Jun;41(2-3):123-31 PMID: 15159057
  13. Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen.
    J Exp Med. 2004 Jul 5;200(1):89-98 PMID: 15238608
  14. Complement C5a receptor is essential for the optimal generation of antiviral CD8+ T cell responses.
    J Immunol. 2004 Aug 15;173(4):2524-9 PMID: 15294968
  15. C5a initiates the inflammatory cascade in immune complex peritonitis.
    J Immunol. 2004 Sep 1;173(5):3437-45 PMID: 15322209
  16. TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function.
    Immunity. 2004 Jul;21(1):107-19 PMID: 15345224
  17. Inflammatory effects of endotoxin-like contaminants in commonly used protein preparations.
    Science. 1977 Apr 1;196(4285):83-5 PMID: 557238
  18. Pulmonary injury induced by C3a and C5a anaphylatoxins.
    Am J Pathol. 1980 Aug;100(2):327-48 PMID: 6967702
  19. Anaphylatoxin-mediated contraction of guinea pig lung strips: a nonhistamine tissue response.
    J Immunol. 1981 Jun;126(6):2258-61 PMID: 6164725
  20. Release of leukotrienes from guinea pig lung stimulated by C5ades Arg anaphylatoxin.
    J Immunol. 1982 May;128(5):2247-52 PMID: 6174625
  21. The role of the complement system in the pathogenesis of multiple organ failure in shock.
    Prog Clin Biol Res. 1989;308:291-7 PMID: 2675054
  22. Interleukin-4 augments production of the third complement component by the alveolar epithelial cell line A549.
    Int Arch Allergy Immunol. 1993;100(1):35-41 PMID: 8428161
  23. Regulation of IgE responses to inhaled antigen in mice by antigen-specific gamma delta T cells.
    Science. 1994 Sep 23;265(5180):1869-71 PMID: 7916481
  24. Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice.
    J Exp Med. 1995 Nov 1;182(5):1527-36 PMID: 7595222
  25. The C5a chemoattractant receptor mediates mucosal defence to infection.
    Nature. 1996 Sep 5;383(6595):86-9 PMID: 8779720
  26. A genome-wide search for asthma susceptibility loci in ethnically diverse populations.
    Nat Genet. 1997 Apr;15(4):389-92 PMID: 9090385
  27. Generation of anaphylatoxins through proteolytic processing of C3 and C5 by house dust mite protease.
    J Allergy Clin Immunol. 1997 Aug;100(2):253-60 PMID: 9275149
  28. Resistance to antigen-induced airway hyperresponsiveness requires endogenous production of IL-12.
    J Immunol. 1998 Jul 15;161(2):919-26 PMID: 9670970
  29. Interleukin-13: central mediator of allergic asthma.
    Science. 1998 Dec 18;282(5397):2258-61 PMID: 9856949
  30. A genome-wide search for linkage to asthma. German Asthma Genetics Group.
    Genomics. 1999 May 15;58(1):1-8 PMID: 10333435
  31. Immunologic basis of antigen-induced airway hyperresponsiveness.
    Annu Rev Immunol. 1999;17:255-81 PMID: 10358759
  32. Selection of a C5a receptor antagonist from phage libraries attenuating the inflammatory response in immune complex disease and ischemia/reperfusion injury.
    J Immunol. 1999 Jul 15;163(2):985-94 PMID: 10395696
  33. Ablation of the SERCA3 gene alters epithelium-dependent relaxation in mouse tracheal smooth muscle.
    Am J Physiol. 1999 Aug;277(2 Pt 1):L264-70 PMID: 10444520
  34. Intranasal exposure of mice to house dust mite elicits allergic airway inflammation via a GM-CSF-mediated mechanism.
    J Immunol. 2004 Nov 15;173(10):6384-92 PMID: 15528378
  35. Variations in the C3, C3a receptor, and C5 genes affect susceptibility to bronchial asthma.
    Hum Genet. 2004 Sep;115(4):295-301 PMID: 15278436
  36. CC chemokine receptor (CCR)3/eotaxin is followed by CCR4/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo.
    J Exp Med. 2000 Jan 17;191(2):265-74 PMID: 10637271
  37. Requirements for C5a receptor-mediated IL-4 and IL-13 production and leukotriene C4 generation in human basophils.
    J Immunol. 2000 Aug 15;165(4):2183-9 PMID: 10925305
  38. Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation.
    J Clin Invest. 2000 Aug;106(4):551-9 PMID: 10953030
  39. A role for the C3a anaphylatoxin receptor in the effector phase of asthma.
    Nature. 2000 Aug 31;406(6799):998-1001 PMID: 10984054
  40. Cutting edge: guinea pigs with a natural C3a-receptor defect exhibit decreased bronchoconstriction in allergic airway disease: evidence for an involvement of the C3a anaphylatoxin in the pathogenesis of asthma.
    J Immunol. 2000 Nov 15;165(10):5401-5 PMID: 11067890
  41. Expression of the complement anaphylatoxin C3a and C5a receptors on bronchial epithelial and smooth muscle cells in models of sepsis and asthma.
    J Immunol. 2001 Feb 1;166(3):2025-32 PMID: 11160252
  42. Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma.
    Nat Immunol. 2000 Sep;1(3):221-6 PMID: 10973279
  43. Enhanced expression of complement C5a receptor mRNA in human diseased kidney assessed by in situ hybridization.
    Kidney Int. 2001 Jul;60(1):137-46 PMID: 11422745
  44. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen.
    Nat Immunol. 2001 Aug;2(8):725-31 PMID: 11477409
  45. Anaphylatoxins and infectious and non-infectious inflammatory diseases.
    Mol Immunol. 2001 Aug;38(2-3):175-87 PMID: 11532279
  46. Cutting edge: the absence of C3 demonstrates a role for complement in Th2 effector functions in a murine model of pulmonary allergy.
    J Immunol. 2001 Oct 15;167(8):4141-5 PMID: 11591733
  47. C5a negatively regulates toll-like receptor 4-induced immune responses.
    Immunity. 2005 Apr;22(4):415-26 PMID: 15845447
  48. Role of C5 in the development of airway inflammation, airway hyperresponsiveness, and ongoing airway response.
    J Clin Invest. 2005 Jun;115(6):1590-600 PMID: 15902311
  49. Complement and Toll-like receptors: key regulators of adaptive immune responses.
    Mol Immunol. 2006 Jan;43(1-2):13-21 PMID: 16019071
  50. Complement factor C5a mediates renal ischemia-reperfusion injury independent from neutrophils.
    J Immunol. 2003 Apr 1;170(7):3883-9 PMID: 12646657
  51. Contribution of anaphylatoxin C5a to late airway responses after repeated exposure of antigen to allergic rats.
    J Immunol. 2001 Oct 15;167(8):4651-60 PMID: 11591795
  52. Complement factors C3a and C5a are increased in bronchoalveolar lavage fluid after segmental allergen provocation in subjects with asthma.
    Am J Respir Crit Care Med. 2001 Nov 15;164(10 Pt 1):1841-3 PMID: 11734433
  53. Conditional gene expression in the respiratory epithelium of the mouse.
    Transgenic Res. 2002 Feb;11(1):21-9 PMID: 11874100
  54. Complement factor 3 mediates particulate matter-induced airway hyperresponsiveness.
    Am J Respir Cell Mol Biol. 2002 Oct;27(4):413-8 PMID: 12356574
  55. Generation of C5a by phagocytic cells.
    Am J Pathol. 2002 Nov;161(5):1849-59 PMID: 12414531
  56. Complement in allergy and asthma.
    Curr Opin Immunol. 2002 Dec;14(6):705-8 PMID: 12413519
  57. Absence of the complement anaphylatoxin C3a receptor suppresses Th2 effector functions in a murine model of pulmonary allergy.
    J Immunol. 2002 Nov 15;169(10):5926-33 PMID: 12421977
  58. Plasmacytoid dendritic cells in immunity.
    Nat Immunol. 2004 Dec;5(12):1219-26 PMID: 15549123
  59. Pharmacological targeting of anaphylatoxin receptors during the effector phase of allergic asthma suppresses airway hyperresponsiveness and airway inflammation.
    J Immunol. 2005 Jan 15;174(2):783-9 PMID: 15634899
  60. Dynamics of dendritic cell phenotype and interactions with CD4+ T cells in airway inflammation and tolerance.
    J Immunol. 2005 Jan 15;174(2):854-63 PMID: 15634907
  61. The complement inhibitory protein DAF (CD55) suppresses T cell immunity in vivo.
    J Exp Med. 2005 Feb 21;201(4):567-77 PMID: 15710649
  62. Role of C5a in inflammatory responses.
    Annu Rev Immunol. 2005;23:821-52 PMID: 15771587
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI26582
Email
[email protected]
Published
2006-03-00
Pages
783-96
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1386108
Subset
IM
Grants
NIAID NIH HHS · R01 AI057839 · United States
NHLBI NIH HHS · R01 HL067736 · United States
NIAID NIH HHS · R01-AI057839 · United States
NHLBI NIH HHS · R01-HL67736 · United States
Corrections
CommentIn
PMID: 16511597
External Links
PubMed source DOI: 10.1172/JCI26582 PMC Full Text View journal details
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