Fcγ Receptor III and Fcγ Receptor IV on Macrophages Drive Autoimmune Valvular Carditis in Mice
Article first published online: 28 MAR 2014
Copyright © 2014 by the American College of Rheumatology
Arthritis & Rheumatology
Volume 66, Issue 4, pages 852–862, April 2014
How to Cite
Hobday, P. M., Auger, J. L., Schuneman, G. R., Haasken, S., Verbeek, J. S. and Binstadt, B. A. (2014), Fcγ Receptor III and Fcγ Receptor IV on Macrophages Drive Autoimmune Valvular Carditis in Mice. Arthritis & Rheumatology, 66: 852–862. doi: 10.1002/art.38311
- Issue published online: 28 MAR 2014
- Article first published online: 28 MAR 2014
- Accepted manuscript online: 10 DEC 2013 02:31PM EST
- Manuscript Accepted: 5 DEC 2013
- Manuscript Received: 27 AUG 2013
- NIH. Grant Numbers: R03-AR-057101, T32-AI-007313, K08-AR-054317
- Viking Children's Fund
- University of Minnesota Department of Pediatrics (award)
- Disease Targeted Innovative Research grant from the Rheumatology Research Foundation
Arthritis and valvular carditis coexist in several human rheumatic diseases, including systemic lupus erythematosus, rheumatic fever, and rheumatoid arthritis. T cell receptor–transgenic K/BxN mice develop spontaneous autoantibody-associated arthritis and valvular carditis. The common Fc receptor γ (FcRγ) signaling chain is required for carditis to develop in K/BxN mice. FcRγ pairs with numerous receptors in a variety of cells. The aim of this study was to identify the FcRγ-associated receptors and Fcγ receptor (FcγR)–expressing cells that mediate valvular carditis in this model.
We bred K/BxN mice lacking the genes that encode activating Fcγ receptors (FcγRI, FcγRIII, and FcγRIV), and we assessed these mice for valvular carditis. We similarly evaluated complement component C3–deficient K/BxN mice. Immunohistochemistry, bone marrow transplantation, and macrophage depletion were used to define the key FcRγ-expressing cell type.
Genetic deficiency of only one of the activating Fcγ receptors did not prevent carditis, whereas deficiency of all 3 activating Fcγ receptors did. Further analysis demonstrated that FcγRIII and FcγRIV were the key drivers of valve inflammation; FcγRI was dispensable. C3 was not required. FcRγ expression by radioresistant cells was critical for valvular carditis to develop, and further analysis indicated that macrophages were the key candidate FcγR-expressing effectors of carditis.
FcγRIII and FcγRIV act redundantly to promote valvular carditis in K/BxN mice with systemic autoantibody-associated arthritis. Macrophage depletion reduced the severity of valve inflammation. These findings suggest that pathogenic autoantibodies engage Fcγ receptors on macrophages to drive valvular carditis. Our study provides new insight into the pathogenesis of cardiovascular inflammation in the setting of autoantibody-associated chronic inflammatory diseases.