Background/Purpose: Cardiovascular (CV) comorbidity is common in rheumatic diseases and includes accelerated atherosclerosis and inflammatory valvular heart disease (iVHD). KRN T cell receptor (TCR) transgenic mice congenically expressing the H-2^g7MHC class II molecule (K/B/g7) develop spontaneous autoimmune arthritis and provide a powerful tool for understanding the effects of chronic inflammation on the cardiovascular system. In particular, K/B/g7 mice develop iVHD with many features mirroring human pathology. By 3 weeks of age their mitral valves (MVs) uniformly demonstrate histological evidence of inflammatory infiltration. By 8 weeks, drastic MV leaflet thickening with increased collagen content and accumulation of inflammatory monocytes is apparent. Here we explored the molecular mechanisms driving iVHD in K/B/g7 mice.

Methods: Serum TNFα and IL-6 are elevated in K/B/g7 mice. Due to the established roles for these cytokines in the pathogenesis of rheumatoid arthritis and iVHD in humans, we hypothesized that they are critical mediators of iVHD in the K/B/g7 model. We used neutralizing monoclonal antibodies to test this hypothesis, treating one cohort of K/B/g7 mice at the time of iVHD onset (4 weeks of age, initiation) and another after iVHD had been established (6 weeks of age, maintenance). The mice were given twice weekly injections of 200 μg mAb blocking TNFα, IL-6, VCAM-1, or α4β1 integrin (very late antigen 4, VLA-4) for 4 weeks. We assessed arthritis severity during the treatment period. The effect of these blocking antibodies on iVHD was determined using histological assessment and immunofluorescent staining and compared to animals that received injections of isotype control mAb.

Results: Neutralization of TNFα or IL-6 prevented iVHD progression. In both cases, this was correlated with significantly reduced expression of VCAM-1 at the blood-endothelial interface and also with significant reductions in arthritis severity. Neutralization of VCAM-1 or α4β1 did not reduce the severity of joint inflammation, but completely prevented induction of iVHD. Interestingly, when used as a treatment for established iVHD, only TNFα and VCAM-1 neutralization reduced iVHD severity, but neither significantly reduced the severity of established arthritis.

Conclusion: These studies identify a TNFα/IL-6-VCAM1-α4β1 axis as a critical driver of iVHD initiation and maintenance in K/B/g7 mice. Ongoing studies utilizing conditional gene knockouts aim to confirm the dominant inflammatory cellular element(s) recruited to the valve tissue via surface expression of α4β1. These results may inform treatment strategies for repurposing existing therapeutics (e.g. natalizumab) to treat iVHD in the setting of systemic rheumatic diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/recruitment-of-circulating-monocytes-by-tnfil-6-induced-expression-of-vascular-cell-adhesion-molecule-1-vcam-1-drives-valvular-inflammation-in-kbg7-mice/