Humans with rheumatoid arthritis (RA) demonstrate greater atherosclerotic burden, leading to increased mortality. Progress in understanding this relationship has been hampered by the lack of a suitable animal model. We found that K/BxAg7 mice develop spontaneous arthritis beginning at 4-5 weeks of age followed by severe aortic atherosclerosis when receiving an atherogenic diet. Thus, for the first time, we introduce a mouse model that faithfully recapitulates both human diseases. This project will utilize K/BxAg7 mice to identify the key cellular mechanisms responsible for the development of atherosclerosis in arthritic mice. We will focus on macrophages, as they are crucial for the pathogenesis of both diseases. An adoptive transfer model in which macrophages are specifically depleted using a CD11b-diphtheria toxin receptor construct will be used to test whether macrophages are required for the development of arthritis and atherosclerosis. It is expected that depletion of macrophages will mitigate both diseases. Monocyte fate as they enter tissues will be tracked using Green Fluorescent Protein reporter mice. It is expected that tissue macrophage accumulation will parallel disease progression. We anticipate that serum, joints, and atherosclerotic lesions from K/BxAg7 mice will express increased levels of inflammatory cytokines and chemokines as measured by luminex assays and flow cytometry. Lastly, we will test the effects of established (TNF and IL-6 receptor antagonists and statins) therapies on the development of arthritis and atherosclerosis in K/BxAg7 animals. We predict that amelioration of both diseases will correlate with a reduction in tissue macrophages.
Patients with rheumatoid arthritis (RA) have reduced life expectancy largely due to increased cardiovascular disease. In this proposal, we generated the first model of RA and atherosclerosis and will use this model to determine the role that macrophages, which are central immune cells, play in both of these diseases.
|Misharin, Alexander V; Cuda, Carla M; Saber, Rana et al. (2014) Nonclassical Ly6C(-) monocytes drive the development of inflammatory arthritis in mice. Cell Rep 9:591-604|
|Cuda, Carla M; Misharin, Alexander V; Gierut, Angelica K et al. (2014) Caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation. J Immunol 192:5548-60|