title: C5a receptor enables participation of mast cells in immune complex arthritis independently of Fcγ receptor modulation.
abstract: OBJECTIVE
  Mast cells are tissue-resident immune sentinels that are implicated in the pathogenesis of inflammatory joint disease. The aim of this study was to test our hypothesis that complement fragments could be key activators of synovial mast cells in autoimmune arthritis.
  
  
  METHODS
  In vivo studies used the murine K/BxN arthritis model, a distal symmetric polyarthritis mediated by IgG immune complexes. Expression of C5aR on synovial mast cells was determined by immunohistochemical and functional studies. C5aR(-/-) and control mast cells were engrafted into mast cell-deficient WBB6 F1-Kit(w) /Kit(W-v) (W/Wv) mice to examine the requirement for this receptor in arthritis. C5aR-dependent activation of mast cells was investigated in C5aR(-/-) animals and in murine and human mast cell cultures.
  
  
  RESULTS
  Murine synovial mast cells express functional C5aR. Unlike their wild-type counterparts, C5aR(-/-) mast cells adoptively transferred into W/Wv mice were not competent to restore arthritis, despite equivalent synovial engraftment. Activation of C5aR(-/-) mast cells by K/BxN serum in vivo remained intact, indicating that C5aR is dispensable for normal IgG-mediated triggering. Consistent with this result, cultured mast cells treated with C5a failed to modulate the expression of Fcγ receptors (FcγR) or to otherwise alter the activation threshold. In human mast cells, C5a promoted the production of the neutrophil chemotaxin interleukin-8, and recruitment of neutrophils at 24 hours after serum administration was impaired in C5aR(-/-) mice, suggesting that enhanced neutrophil chemoattractant production underlies the requirement for C5aR on mast cells in arthritis.
  
  
  CONCLUSIONS
  Stimulation via C5aR is required to unleash the proinflammatory activity of synovial mast cells in immune complex arthritis, albeit via a mechanism that is distinct from C5a-modulated expression of FcγR.
authors.affiliation: Brigham and Women's Hospital and Children's Hospital Boston, Boston, Massachusetts, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Nigrovic
authors.forename: Odile
authors.initials: O
authors.lastname: Malbec
authors.forename: Bao
authors.initials: B
authors.lastname: Lu
authors.forename: Maciej M
authors.initials: MM
authors.lastname: Markiewski
authors.forename: Chris
authors.initials: C
authors.lastname: Kepley
authors.forename: Norma
authors.initials: N
authors.lastname: Gerard
authors.forename: Craig
authors.initials: C
authors.lastname: Gerard
authors.forename: Marc
authors.initials: M
authors.lastname: Daëron
authors.forename: David M
authors.initials: DM
authors.lastname: Lee
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology / Q000378:metabolism; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D020556:Neutrophil Infiltration / Q000276:immunology; D044087:Receptor, Anaphylatoxin C5a / Q000276:immunology / Q000378:metabolism*; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000936:Antigen-Antibody Complex; D044087:Receptor, Anaphylatoxin C5a; D017452:Receptors, IgG