Trained immunity as a link between Inflammatory Arthritis and development of Cardiovascular Disease

SUMMARY Trained immunity describes the relatively new observation that exposure to inflammation alters the innate immune cells, monocytes and neutrophils, to alter their behavior such that they respond to a second stimuli with more efficiency. This process is akin to the immunologic memory of the adaptive

immune system. Initially observed in response to pathogens and vaccination, it is now increasingly clear that sterile, chronic inflammation leads to systemic reprogramming of macrophages. While developed to improve efficiency of pathogen clearance, this mechanism comes at the cost of promoting cardiovascular disease. Rheumatoid arthritis (RA), a common, chronic autoimmune disease, carries

the burden of premature mortality to cardiovascular disease. No studies have directly tested whether inflammatory RA induces trained immune responses in innate cells of the arthritic joint or in the aortic wall. This proposal hypothesizes that trained immunity occurs in response to RA in the macrophages

of the joint and in the bone marrow. Additionally, we propose that this training of the innate immune system causes the macrophages of the aorta to become pro-atherogenic, and thus promote development of atherosclerosis. The overarching hypothesis of this proposal is that trained immunity is a novel cause behind the increased incidence of cardiovascular disease in RA patients, and proposes

to test this hypothesis using murine models. The PI is a K01 awardee in her 4th year of funding and will use these pilot studies to pursue her long term research goal to pursue mechanisms linking RA and cardiovascular disease. Indeed, these studies will provide the pilot data necessary to pursue independent R01 funding exploring the links between inflammatory arthritis, trained immunity, and

cardiovascular disease.