title: Involvement of Mast Cells in α7 Nicotinic Receptor Agonist Exacerbation of Freund's Complete Adjuvant-Induced Monoarthritis in Mice.
abstract: OBJECTIVE
  Activation of antiinflammatory cholinergic (vagal) pathways can reduce inflammation, and in vitro studies support a pivotal role of α7 nicotinic acetylcholine receptors (α7-nAChR), macrophages, and T cells in these events. The aim of this study was to assess α7-nAChR agonists as an antiinflammatory treatment for Freund's complete adjuvant (CFA)-induced monoarthritis.
  
  
  METHODS
  Arthritis was induced by intraarticular injection of CFA unilaterally into the knee joints of mice. Animals were treated with α7-nAChR agonists (AR-R17779 or A844606), with or without antagonists (COG133 or methyllycaconitine), and joint inflammation and pain were assessed. Experiments were repeated in c-Kit(W-sh) mast cell-deficient mice, and the effects of an α7-nAChR agonist on mast cell proliferation, migration, and activation by lipopolysaccharide (LPS) were tested.
  
  
  RESULTS
  Treatment with α7-nAChR agonists significantly exacerbated CFA-induced arthritis and pain, as gauged by all indices of assessment, the specificity of which was confirmed by coadministration of an nAChR antagonist that attenuated the increase in disease severity. Toluidine blue-positive mast cells were increased in the joint capsule of CFA plus AR-R17779-treated mice, and AR-R17779 enhanced LPS-induced TNF proliferation and migration of a human mast cell line. The AR-R17779-driven increase in severity of CFA-induced arthritis was significantly reduced in mast cell-deficient mice.
  
  
  CONCLUSIONS
  Using CFA to elicit a local inflammatory response, we found that pharmacologic activation of α7-nAChR exacerbated joint inflammation and pain, in part via mast cells, which illustrates the organ- and disease-specific nature of regulatory neuroimmune mechanisms. Thus, α7-nAChR activation may not be uniformly antiinflammatory in all types of inflammatory joint disease.
authors: University of Calgary, Calgary, Alberta, Canada.
authors: Fernando
authors: F
authors: Lopes
authors: University of Calgary, Calgary, Alberta, Canada.
authors: Rabea
authors: R
authors: Graepel
authors: University of Calgary, Calgary, Alberta, Canada.
authors: Jose Luis
authors: JL
authors: Reyes
authors: University of Calgary, Calgary, Alberta, Canada.
authors: Arthur
authors: A
authors: Wang
authors: University of Calgary, Calgary, Alberta, Canada.
authors: Björn
authors: B
authors: Petri
authors: Dalhousie University, Halifax, Nova Scotia, Canada.
authors: Jason J
authors: JJ
authors: McDougall
authors: University of Calgary, Calgary, Alberta, Canada.
authors: Keith A
authors: KA
authors: Sharkey
authors: University of Calgary, Calgary, Alberta, Canada.
authors: Derek M
authors: DM
authors: McKay
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000633:toxicity; D000818:Animals; D001057:Apolipoproteins E / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000276:immunology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005620:Freund's Adjuvant / Q000633:toxicity; D007249:Inflammation; D007270:Injections, Intra-Articular; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*; D044004:Xanthones / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
chemical_list: C528720:2-(5-methylhexahydropyrrolo(3,4-c)pyrrol-2-yl)xanthen-9-one; C408128:AR-R 17779; D000276:Adjuvants, Immunologic; D001057:Apolipoproteins E; D001952:Bridged-Ring Compounds; D008070:Lipopolysaccharides; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D011758:Pyrroles; D013141:Spiro Compounds; D044004:Xanthones; D064569:alpha7 Nicotinic Acetylcholine Receptor; C579624:apolipoprotein E (133-149); C054634:methyllycaconitine; D005620:Freund's Adjuvant; D000157:Aconitine