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Involvement of Mast Cells in α7 Nicotinic Receptor Agonist Exacerbation of Freund's Complete Adjuvant-Induced Monoarthritis in Mice.
Arthritis Rheumatol. 2016 Feb; 68(2):542-52.AR

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.

CONCLUSION

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+Show Affiliations

University of Calgary, Calgary, Alberta, Canada.University of Calgary, Calgary, Alberta, Canada.University of Calgary, Calgary, Alberta, Canada.University of Calgary, Calgary, Alberta, Canada.University of Calgary, Calgary, Alberta, Canada.Dalhousie University, Halifax, Nova Scotia, Canada.University of Calgary, Calgary, Alberta, Canada.University of Calgary, Calgary, Alberta, Canada.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26314943

Citation

Lopes, Fernando, et al. "Involvement of Mast Cells in Α7 Nicotinic Receptor Agonist Exacerbation of Freund's Complete Adjuvant-Induced Monoarthritis in Mice." Arthritis & Rheumatology (Hoboken, N.J.), vol. 68, no. 2, 2016, pp. 542-52.
Lopes F, Graepel R, Reyes JL, et al. Involvement of Mast Cells in α7 Nicotinic Receptor Agonist Exacerbation of Freund's Complete Adjuvant-Induced Monoarthritis in Mice. Arthritis Rheumatol. 2016;68(2):542-52.
Lopes, F., Graepel, R., Reyes, J. L., Wang, A., Petri, B., McDougall, J. J., Sharkey, K. A., & McKay, D. M. (2016). Involvement of Mast Cells in α7 Nicotinic Receptor Agonist Exacerbation of Freund's Complete Adjuvant-Induced Monoarthritis in Mice. Arthritis & Rheumatology (Hoboken, N.J.), 68(2), 542-52. https://doi.org/10.1002/art.39411
Lopes F, et al. Involvement of Mast Cells in Α7 Nicotinic Receptor Agonist Exacerbation of Freund's Complete Adjuvant-Induced Monoarthritis in Mice. Arthritis Rheumatol. 2016;68(2):542-52. PubMed PMID: 26314943.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Involvement of Mast Cells in α7 Nicotinic Receptor Agonist Exacerbation of Freund's Complete Adjuvant-Induced Monoarthritis in Mice. AU - Lopes,Fernando, AU - Graepel,Rabea, AU - Reyes,Jose Luis, AU - Wang,Arthur, AU - Petri,Björn, AU - McDougall,Jason J, AU - Sharkey,Keith A, AU - McKay,Derek M, PY - 2015/02/13/received PY - 2015/08/25/accepted PY - 2015/8/29/entrez PY - 2015/9/1/pubmed PY - 2016/6/15/medline SP - 542 EP - 52 JF - Arthritis & rheumatology (Hoboken, N.J.) JO - Arthritis Rheumatol VL - 68 IS - 2 N2 - 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. CONCLUSION: 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. SN - 2326-5205 UR - https://www.unboundmedicine.com/medline/citation/26314943/Involvement_of_Mast_Cells_in_α7_Nicotinic_Receptor_Agonist_Exacerbation_of_Freund's_Complete_Adjuvant_Induced_Monoarthritis_in_Mice_ L2 - https://doi.org/10.1002/art.39411 DB - PRIME DP - Unbound Medicine ER -