Date: Monday, November 6, 2017
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Cardiovascular comorbidity is significant in patients with systemic autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosus . T cell receptor transgenic K/B.g7 mice develop autoimmune arthritis and concomitant inflammatory and fibrotic valvular heart disease (VHD) with complete penetrance. This model allows dissection of the molecular and cellular pathways that drive accelerated cardiovascular disease in the setting of systemic autoimmunity. We have previously demonstrated that VHD in K/B.g7 mice is orchestrated by discrete mononuclear phagocyte populations with CD301b+ tissue-reparative macrophages comprising the dominant valve-infiltrating population. We have also demonstrated that a TNF/IL6-VCAM1-VLA4 axis drives disease. Here we sought to assess the specific contribution of mononuclear phagocytes (MNPs) in this disease process, using a conditional gene knockout approach.
To test the hypothesis that MNPs responding to circulating autoantibodies provide the source of TNF and IL6 during mitral valve disease (MVD) initiation, we first generated a Cx3cr1-Cre:Sykfl/fl K/B.g7 line to prevent FcγR-mediated MNP activation. Histological assessment of valve disease severity and flow-cytometric assessment of TNF and IL6 production from valve-infiltrating and lymphoid MNPs were employed. Secondly, to test the hypothesis that recruitment of circulating MNPs drives MVD progression through VLA4-VCAM1 interactions, we generated a Cx3cr1-Cre:Itga4fl/fl K/B.g7 line to disrupt this interaction. Valve inflammation and fibrosis were quantified histologically. Cre-negative littermates were employed as controls in all cases.
Deletion of Syk in from MNPs ameliorated MVD severity and was accompanied by impaired TNF and IL6 production by valve infiltrating macrophages. Interestingly, lymphoid-resident MNP cytokine production was unaffected. Impairing MNP recruitment through deletion of VLA4 (Itga4) significantly attenuated the severity of K/B.g7 cardiac valve inflammation and fibrosis.
These studies define the critical molecular pathways used by MNPs to promote cardiovascular pathology in the setting of systemic autoimmunity. We have defined multiple therapeutic targets (TNF, IL6, Syk, VLA4, VCAM1) that could be exploited for the treatment of the cardiovascular comorbidity that accompanies human rheumatic diseases. Ongoing studies are aimed at clarifying the molecular pathways governing MNP-mediated matrix production following their infiltration to the valve stroma.
To cite this abstract in AMA style:Meier L, Auger JL, Engelson BJ, Cowan H, Breed E, Gonzalez-Torres M, Boyer J, Binstadt BA. Mononuclear Phagocytes Mediate Systemic Autoimmune Disease-Related Valvular Heart Disease Via Inflammatory Cytokine Production and Recruitment of Tissue-Reparative macrophages [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/mononuclear-phagocytes-mediate-systemic-autoimmune-disease-related-valvular-heart-disease-via-inflammatory-cytokine-production-and-recruitment-of-tissue-reparative-macrophages/. Accessed September 25, 2021.
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