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Abstract Number: 1007

Macrophage Mediators of Autoimmune Valvular Carditis and Fibrosis

Lee Meier1, Mayra Gonzalez-Torres2, Jennifer L. Auger2, Aubyn Marath3 and Bryce A. Binstadt2, 1Department of Pediatrics and Center for Immunology, University of Minnesota, Minneapols, MN, 2Department of Pediatrics and Center for Immunology, University of Minnesota, Minneapolis, MN, 3CardioStart International, Tampa, FL

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Animal models, Arthritis, autoantibodies and cardiovascular disease, Macrophage

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Session Information

Date: Monday, October 22, 2018

Title: Innate Immunity Poster

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.


Disclosure: L. Meier, None; M. Gonzalez-Torres, None; J. L. Auger, None; A. Marath, None; B. A. Binstadt, None.

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 9). https://acrabstracts.org/abstract/macrophage-mediators-of-autoimmune-valvular-carditis-and-fibrosis/. Accessed .
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