Immunological diseases such as Systemic Lupus Erythematosus (SLE) are driven by disruption of regulatory mechanisms in both T and B lymphocytes leading to autoantibody production and inflammation. As autoantibodies promote a variety of SLE-associated pathologies, including immune complex formation and deposition responsible for vasculitis and glomerulonephritis, many therapeutic approaches to treat SLE have targeted B cell survival or function. However, effectiveness can be limited and secondary toxicities can be severe. A new approach may be to interfere with the basic metabolic processes necessary for lymphocyte growth and function. We have shown that cellular metabolism is highly regulated in lymphocyte activation and that while resting T cells rely on an oxidative metabolism, activation leads to a metabolic reprogramming to greatly increase glycolysis. Inhibition of glycolysis in T cells can prevent their effector function. It is likely that B cells lso undergo metabolic reprogramming that is essential for activation and effector function that may allow targeting of B cell metabolism to suppress autoantibody production. To test this new direction for treatment of rheumatic diseases, it is essential to understand B cell metabolism and how changes in metabolism impact B cell tolerance and autoimmunity. In our preliminary studies, we show that B cells do undergo a metabolic reprogramming upon activation to increase glycolysis and lactate production and inhibition of this metabolic transition prevents antibody production. Importantly, B cells from SLE-prone BAFF-transgenic mice were highly glycolytic immediately upon isolation, suggesting that this metabolic transition occurs in vivo coincident with autoantibody production and disease. A key regulator of glucose metabolism is Pyruvate Dehydrogenase Kinase 1 (PDHK1), which provides an inhibitory phosphorylation of Pyruvate Dehydrogenase (PDH) and directs pyruvate conversion into lactate to elevate glycolysis. We show that inhibition of PDHK1 can reduce B cell glycolysis and antibody production. B cell metabolism has not the focus of previous immunological studies and we propose to evaluate the potential of targeting this process to suppress autoantibody production and disease in SLE. We hypothesize that high rates of glycolysis are essential for B cell autoantibody production and that PDHK1 will provide a new metabolic target to suppress B cell proliferation and autoreactivity to treat inflammatory and autoantibody-mediated diseases, such as SLE. To test this hypothesis we will: (1) Establish if metabolic reprogramming of B cells to become highly glycolytic is required for antibody production;and (2) Test if modulation of glucose metabolism by PDHK1 inhibition impacts B cell autoreactivity in vitro and in vivo. Together, these studies are the first to directly focus on mechanisms of B cell metabolism and also to test the potential of pharmacological manipulation of PDHK1 to target metabolism and suppress B cell autoreactivity and autoantibody production in SLE.
Systemic Lupus Erythematosus (SLE) is characterized by B cell production of autoantibodies that drive disease pathology. We have found that lymphocyte metabolism is highly dynamic and exerts strong regulation over cellular effector functions, such as autoantibody production. This study will establish the regulation and role of glucose metabolism in B cell activation and secretion of autoantibody to determine if targeting B cell metabolism may provide a new therapeutic direction in SLE.
|Kishton, Rigel J; Barnes, Carson E; Nichols, Amanda G et al. (2016) AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival. Cell Metab 23:649-62|
|Kishton, Rigel J; Rathmell, Jeffrey C (2015) Novel therapeutic targets of tumor metabolism. Cancer J 21:62-9|
|Macintyre, Andrew N; Gerriets, Valerie A; Nichols, Amanda G et al. (2014) The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab 20:61-72|
|Liu, T; Kishton, R J; Macintyre, A N et al. (2014) Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis. Cell Death Dis 5:e1470|
|Caro-Maldonado, Alfredo; Wang, Ruoning; Nichols, Amanda G et al. (2014) Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J Immunol 192:3626-36|