Monocytes and macrophages are essential for tissue and metabolic homeostasis, but in the context of metabolic disorders become dysfunctional and promote chronic inflammatory diseases, including obesity and atherosclerosis. Monocyte and macrophage dysfunction has emerged as a fundamental process common to many chronic inflammatory diseases associated with metabolic disorders, and thus has become a major focus for the design of new pharmacological and therapeutic interventions.
My federally funded research programs are shaping this cutting-edge and rapidly expanding field. We employ a wide array of biochemical, cell biological, redox proteomics, imaging, animal models and translational approaches to explore novel aspects of macrophage biology in the context of human vascular diseases, obesity and diabetic complications. Our approach is to build on fundamental discoveries at the molecular and cellular level and to translate these into animal models and ultimately, into patient settings.
Methods and Technologies
My group currently pursues three main lines of research. They 1) address the molecular mechanisms of thiol redox signaling in monocytes and macrophages and their dysregulation by metabolic stress, 2) explore the roles for ursolic acid and related triterpenoids in the prevention and treatment of obesity and micro- and macrovascular diseases associated with metabolic disorders, and 3) we seek to develop new molecular imaging reagents targeting tissue macrophages for the non-invasive detection and monitoring of atherosclerosis and aneurysms.
Intracellular Protein Thiols as Sensors of the Extracellular Metabolic Environment: Role of Protein S-Glutathionylation in Regulating Monocyte and Macrophage Metabolism, Signaling, Function and Phenotypic Fate
Chemokine-driven transmigration of monocytes into the subendothelial space is a fundamental and rate-limiting process in atherogenesis. According to current paradigms, the extent of monocyte recruitment into the vasculature is primarily dependent on 1) monocyte adhesion initiated by activated or “injured” endothelium, and 2) the chemokine gradient generated by the injured vessel wall that drives monocyte transmigration and macrophage accumulation. We have now uncovered a novel third component: A thiol redox-sensitive mechanism in monocytes that upon dysregulation by metabolic disorders, “primes” and transforms monocytes into a hyper-chemotactic, pro-inflammatory phenotype that gives rise to dysfunctional macrophages. We have shown that in mice, and very recently in baboons, chemotactic activity of monocytes increases with increasing hyperlipidemia and hyperglycemia, and is associated with accelerated macrophage recruitment. Importantly, monocyte priming not only accelerates atherosclerotic lesion formation but also promotes obesity, kidney disease and liver steatosis in mice. Our recent studies may have identified the molecular basis for the well-established associations between metabolic disorders, oxidative stress, and a wide array of diseases that involve the recruitment monocyte-derived macrophages, including atherosclerosis, obesity, impaired myocardial healing, and heart failure after myocardial infarction, as well as diabetic complications such as renal disease and impaired wounds healing. We are in the process of identifying the key pathways dysregulated by monocyte priming and elucidating the molecular mechanisms underlying metabolic stress-induced monocyte dysfunction and reprogramming.
New Dietary Intervention Strategies based on Ursolic acid and its Analogues for Risk Reduction and the Prevention of Obesity, Cardiovascular Diseases and Diabetic Complications
Metabolic disorders including obesity, dyslipidemia, and diabetes appear to be associated with monocyte dysfunction, yet the molecular mechanisms underlying monocyte dysfunction in vivo are only poorly understood. Our recent studies have shown that metabolic stress promotes the dysregulation and hyper-activation of monocyte responses to chemokines, a process we coined “metabolic priming” (see above). We discovered that dietary supplementation of mice with ursolic acid, a triterpenoid with anti-inflammatory properties, or its analogue, 23-hydroxyursolic urosolic acid, protects blood monocytes against metabolic priming and dysfunction. Both compounds dramatically attenuate macrophage recruitment to sites of inflammation and protect mice from atherosclerosis, diabetic kidney diseases and against diet-induced obesity. We have identified and are in the process of validating several novel potential molecular targets for the anti-atherogenic and anti-inflammatory activity of ursolic acid and 23-hydroxyursolic urosolic acid. We recently filed a patent for 23-hydroy ursolic acid and plan to synthesize and test additional novel compounds.
A new mechanism-based dietary supplement that is both relatively inexpensive and safe would greatly benefit populations at high risk for diabetes and diabetic complications such as Hispanic/Latino Americans, who are 1.7-times more likely to have diabetes than are non-Hispanic whites. The availability of such low-cost dietary supplements for the prevention and treatment of obesity and diabetic complications therefore would have a very significant impact on our current disease prevention efforts.
Targeting Macrophages in the Blood Vessel: Molecular Imaging for the Detection and Monitoring of Vascular Inflammation, Vulnerable Plaque and Aortic Aneurysms
Conventional cardiovascular imaging is limited when it comes to the early detection of pathological processes within the vessel wall that have not yet caused significant luminal stenosis. In contrast, molecular imaging has the potential to track early biological events prior to the onset of structural changes, allowing for the early detection of disease, risk stratification of patients, and noninvasive monitoring of disease progression and response to therapy. Two of the earliest events in vascular inflammation and injury are the transmigration into the vessel wall and the differentiation and activation of monocyte-derived macrophages. Various approaches have been employed to track monocyte trafficking and macrophage activation as pivotal events in the development and progression of vascular diseases. These include direct labeling of the monocytes, detection of enhanced metabolic or phagocytic activities, and specific targeting of cell surface proteins or secreted proteolytic enzymes such as matrix metalloproteinases (MMP). However, these approaches have critical limitations, including the binding and uptake of the targeting agent by circulating monocytes and macrophage-rich organs, limited specificity for activated macrophages, limited depth of penetration into the lesions, and insufficient uptake of the “tracer” for non-invasive in vivo detection. We have synthesized and patented a novel peptide that specifically targets newly recruited and activated macrophages.