Berger Lab Research
The research in the Berger Lab focuses on cell biological processes relevant to atherosclerosis, thrombosis and hemostasis, platelet biology and different phenotypes of cardiovascular diseases. The methods of investigation span the research continuum – from basic laboratory science to translational and clinical research and ultimately patient related outcomes. Genomics and transcriptomics are used in an unbiased manner to create new hypotheses and then test these new observations using the latest molecular techniques including in vitro cell models of thrombosis and coagulation. Large data is also leveraged to examine population outcomes which ultimately is designed to improve patient care.
Some ongoing work from the lab includes:
- The measurement of platelet activity in patients with different high risk vascular phenotypes, such as coronary artery disease, peripheral atherosclerosis, aneurysmal disease, venous disease, diabetes, SLE and HIV;
- Define the role of platelets in women with different types of heart attacks;
- Study platelets as effector cells – investigating how platelets affect endothelial cells, monocytes and macrophages, and smooth muscle cells;
- Regulation of platelet activity in the perioperative period and the ability of platelets to predict the risk of thrombosis and /or bleeding in the post-operative period;
- The clinical and platelet response to antiplatelet and antithrombotic therapeutics; and
- The study of personalized medicine using the platelet phenotype to guide therapeutics
Platelet regulation of myeloid suppressor of cytokine signaling 3 accelerates atherosclerosis
Tessa J. Barrett, Martin Schlegel, Felix Zhou, Mike Gorenchtein, Jennifer Bolstorff, Kathryn J. Moore, Edward A. Fisher and Jeffrey S. Berger
Platelets are best known as mediators of hemostasis and thrombosis; however, their inflammatory effector properties are increasingly recognized. Atherosclerosis, a chronic vascular inflammatory disease, represents the interplay between lipid deposition in the artery wall and unresolved inflammation. Here, we reveal that platelets induce monocyte migration and recruitment into atherosclerotic plaques, resulting in plaque platelet-macrophage aggregates. In Ldlr−/− mice fed a Western diet, platelet depletion decreased plaque size and necrotic area and attenuated macrophage accumulation. Platelets drive atherogenesis by skewing plaque macrophages to an inflammatory phenotype, increasing myeloid suppressor of cytokine signaling 3 (SOCS3) expression and reducing the Socs1:Socs3 ratio. Platelet-induced Socs3 expression regulates plaque macrophage reprogramming by promoting inflammatory cytokine production (Il6, Il1b, and Tnfa) and impairing phagocytic capacity, dysfunctions that contribute to unresolved inflammation and sustained plaque growth. Translating our data to humans with cardiovascular disease, we found that women with, versus without, myocardial infarction have up-regulation of SOCS3, lower SOCS1:SOCS3, and increased monocyte-platelet aggregate. A second cohort of patients with lower extremity atherosclerosis demonstrated that SOCS3 and the SOCS1:SOCS3 ratio correlated with platelet activity and inflammation. Collectively, these data provide a causative link between platelet-mediated myeloid inflammation and dysfunction, SOCS3, and cardiovascular disease. Our findings define an atherogenic role of platelets and highlight how, in the absence of thrombosis, platelets contribute to inflammation.