Systemic autoantibody-mediated diseases accelerate chronic cardiovascular disease in humans. In the K/B.g7 mouse model of spontaneous autoantibody-mediated inflammatory arthritis, valvular carditis arises in part because of Fc receptor-mediated activation of macrophages, leading to production of pathogenic TNF and IL-6. In this study, we explored whether impaired efferocytosis mediated by the interaction of CD47-expressing apoptotic cells with signal regulatory protein α (SIRPα) on macrophages contributes to disease progression in this model. CD47-expressing apoptotic cells and SIRPα+ macrophages were abundant in inflamed/rheumatic cardiac valves from both mice and humans. In vivo anti-CD47 blockade both prevented and treated valvular carditis in K/B.g7 mice. Blocking CD47 enhanced macrophage efferocytosis and reduced macrophage production of TNF and IL-6. These studies highlight the CD47:SIRPα interaction as a key driver of chronic cardiac valve inflammation and suggest these molecules as potential therapeutic targets to reduce cardiovascular disease risk in autoantibody-driven inflammatory diseases.
Bibliographical noteFunding Information:
This work was supported by the U.S. Department of Health and Human Services (HHS), National Institutes of Health (NIH) Grants R01-HL121093, T32-AI007313, T32-GM008244, and T32-HL144472; the Rheumatology Research Foundation (Innovative Research Grant, Medical and Graduate Student Preceptorship); a Dr.Warren & Henrietta Warwick Fellowship; the National Center
© 2022 by TheAmericanAssociation of Immunologists, Inc.
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't