Pulmonary hypertension (PH) refers to a collection of vascular diseases that are characterized by increased arterial pressure in the lung, which can subsequently lead to heart failure and possibly death. It is not clear how PH develops or how early events in the disease correlate with later phenotypes. In this episode, Stephen Chan discusses work from his laboratory that links increased vascular stiffness to altered glutamine metabolism in the pathogenesis of PH. The results of this study provide important insight into the development of PH and identify metabolic pathways that have potential as therapeutic targets for PH.
Alexander Rudensky’s research has defined regulatory T cells and the roles they play in autoimmunity, tolerance, allergies, infections, and cancer. After completing his PhD in Moscow in the early 1980s, Rudensky moved to the United States to study T cells under the mentorship of Charles Janeway. He is currently a professor of immunology at the Memorial Sloan Kettering Cancer Center. JCI Editor at Large Ushma Neill interviews Dr. Rudensky about his childhood in the Soviet Union and his early interest in mathematics and science. He discusses the mentors and coworkers who have shaped his research interests over time, and speculates about the immunological discoveries we can expect in years to come.
Atherosclerosis is a hardening of the arterial wall as the result of cholesterol accumulation. Macrophages deposit LDL-derived cholesterols via pinocytotis; therefore, preventing macrophage-mediated lipid deposition has potential to limit disease progression. In this episode, Takuro Miyazaki and colleagues reveal that elevation of calpain-6 in macrophages promotes atherogenic functions by disrupting CWC22/EJC/Rac1 signaling. Moreover, loss of calpain-6 in murine models was atheroprotective, suggesting that targeting this pathway has therapeutic potential for atherosclerosis.
Some patients with diabetes develop diabetic kidney disease (DKD), which can progress to a loss of renal function. High levels of TNF are predictive of disease and organ damage; however, it is not clear how elevated TNF promotes injury. In this episode, Alessia Fornoni reveals that TNF promotes free cholesterol–dependent podocyte apoptosis via an NFATc1/ ABCA1-dependent mechanism. The results of this study indicate that agents targeting cholesterol efflux should be further explored for treating proteinuric kidney diseases.
During sepsis, there is a progression from a hyperactive immune response to an immunosuppressive state that is characterized by macrophage reprogramming. However, the factors that drive this macrophage response are not well defined. In this episode, Dimitrios Balomenos and Gorjana Rackov discuss their recent study, which shows that p21 is instrumental in macrophage switching from a pro-inflammatory to an immunosuppressive state during sepsis. The results of this study reveal that p21 regulates the balance between p50-p50 and p65-p50 NF-κB during sepsis and provides a potential therapeutic target for this complex condition.