Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: K/B.g7 TCR transgenic mice spontaneously develop both autoimmune arthritis and valvular carditis. We utilize this model to define mediators of rheumatic disease-associated cardiovascular inflammation and fibrosis. We recently demonstrated that CX3CR1- and CD301b-expressing macrophages are critical drivers of valvular carditis in this system. Here we investigated the molecules that these macrophages use to promote cardiovascular inflammation.
Methods: We evaluated specific macrophage activation pathways using whole-animal and macrophage-specific (CX3CR1) conditional gene deletion, as well as in vivo antibody-blocking studies. We focused on prototypic M1 macrophage-associated molecules (IFNg, TLR4, iNOS, IRF5) and on M2 macrophage-associated molecules (IL-4, IL-13, IL-4Rα). We used immunofluorescent staining and flow cytometry to identify key cell types in the inflamed mitral valves of K/B.g7 mice as well in valve specimens from patients with rheumatic heart disease (RHD).
Results: Arthritis and valvular carditis develop normally in K/B.g7 mice lacking the M1-associated genes Ifng, Tlr4, or Nos2 and or with macrophage-specific deletion of the M1 transcription factor IRF5. In contrast, macrophage-specific deletion of IL-4Rα appears to protect K/B.g7 mice from valvular carditis without influencing the development of arthritis. IL-4Rα and IL-13Rα1 are highly expressed in the inflamed valves of K/B.g7 mice and in human patients with RHD. Blockade of IL-13 but not IL-4 reduces valve inflammation.
Conclusion: Valvular carditis in K/B.g7 mice depends on CD301b- and IL-4Rα-expressing macrophages but not on canonical M1 macrophage-associated molecules. IL-13 is a critical driver of disease in this model and may also be involved in human RHD. We speculate that targeting this pathway could reduce rheumatic disease-related cardiovascular disease.
To cite this abstract in AMA style:Meier L, Gonzalez-Torres M, Auger JL, Marath A, Binstadt BA. Macrophage Mediators of Autoimmune Valvular Carditis and Fibrosis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/macrophage-mediators-of-autoimmune-valvular-carditis-and-fibrosis/. Accessed August 14, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/macrophage-mediators-of-autoimmune-valvular-carditis-and-fibrosis/