SBCVD · Role of stress-induced modulation of B cell function in cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of global morbidity and mortality. While psychological stress is a known cardiovascular risk factor, the mechanism by which the brain translates stress into CVD is poorly understood. The underlying cause of CVD is a chronic inflammatory disease called atherosclerosis, the progression and exacerbation of which have been strongly associated with the immune system, including B cells. B cells perform many functions including production of antibodies that provide immunity against disease and cytokines that modulate leukocyte function. However, it remains unknown whether B cells mediate the effects of stress on CVD. Recent studies from Prof. Filip Swirski’s lab show that stress profoundly affects the number and distribution of B cells in the body via a mechanism dependent on the activation of the hypothalamic-pituitary-adrenal axis. In this proposal, I will test the hypothesis that stress aggravates atherosclerosis by modulating B cell function. To recapitulate stress, I will employ a combination of optogenetic and chemogenetic approaches available in the Swirski lab to target specific regions in the brain and characterize the subsequent impact on the phenotype and functional diversity of B cells. I will then identify the B cell-specific mechanisms that mediate the effects of stress on the progression of CVD in Prof. Christoph Binder’s lab, thus facilitating the transfer of knowledge between USA and Europe. With the combined complementary expertise of the two labs, this project will be the first demonstration of the use of state-of-the-art neurological tools to address cardio-immunological questions with a systems biological approach. This approach will not only delineate potential therapeutic targets for immunomodulation of B cells in preventing and treating CVD, but will also provide a direct mechanistic link between stress and chronic inflammation, a general concept with implications beyond atherosclerosis.