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.
|Mandelin 2nd, Arthur M; Homan, Philip J; Shaffer, Alexander M et al. (2018) Transcriptional Profiling of Synovial Macrophages Using Minimally Invasive Ultrasound-Guided Synovial Biopsies in Rheumatoid Arthritis. Arthritis Rheumatol 70:841-854|
|Tsai, FuNien; Homan, Philip J; Agrawal, Hemant et al. (2017) Bim suppresses the development of SLE by limiting myeloid inflammatory responses. J Exp Med 214:3753-3773|
|Zheng, Zhikun; Chiu, Stephen; Akbarpour, Mahzad et al. (2017) Donor pulmonary intravascular nonclassical monocytes recruit recipient neutrophils and mediate primary lung allograft dysfunction. Sci Transl Med 9:|
|Ratsimandresy, Rojo A; Chu, Lan H; Khare, Sonal et al. (2017) The PYRIN domain-only protein POP2 inhibits inflammasome priming and activation. Nat Commun 8:15556|
|Huang, Qi-Quan; Birkett, Robert; Doyle, Renee E et al. (2017) Association of Increased F4/80high Macrophages With Suppression of Serum-Transfer Arthritis in Mice With Reduced FLIP in Myeloid Cells. Arthritis Rheumatol 69:1762-1771|
|Makinde, Hadijat M; Just, Talia B; Cuda, Carla M et al. (2017) The Role of Microglia in the Etiology and Evolution of Chronic Traumatic Encephalopathy. Shock 48:276-283|
|Makinde, Hadijat M; Cuda, Carla M; Just, Talia B et al. (2017) Nonclassical Monocytes Mediate Secondary Injury, Neurocognitive Outcome, and Neutrophil Infiltration after Traumatic Brain Injury. J Immunol 199:3583-3591|
|Li, Kun-Po; Fähnrich, Anke; Roy, Eron et al. (2017) Temporal Expression of Bim Limits the Development of Agonist-Selected Thymocytes and Skews Their TCR? Repertoire. J Immunol 198:257-269|
|Brazee, Patricia L; Soni, Pritin N; Tokhtaeva, Elmira et al. (2017) FXYD5 Is an Essential Mediator of the Inflammatory Response during Lung Injury. Front Immunol 8:623|
|Tsai, FuNien; Perlman, Harris; Cuda, Carla M (2017) The contribution of the programmed cell death machinery in innate immune cells to lupus nephritis. Clin Immunol 185:74-85|
Showing the most recent 10 out of 25 publications