Michelle R. Lennartz
University of Michigan School of Medicine, Ann Arbor
Macrophages play a major role in health and disease. They recognize and destroy invading pathogens, contribute to chronic inflammatory diseases such arthritis and atherosclerosis, and support the growth tumor cells. Our research focuses on the cell biology of macrophages, using an IgG-phagocytosis system to model uptake and killing of pathogens as well as to study the underlying causes of the atherosclerotic plaque rupture (stroke). Additionally, we are collaborating with the pulmonary group to study the macrophages that associate with tumor cells in lymph nodes positive lung cancer.
Infectious disease: We have identified protein kinase C-epsilon (PKC-e) as an important signaling model in bacterial clearance. Mice lacking PKC-e succumb to bacterial infections cleared by their wild type counterparts. We are using an animal model of sepsis (an aberrant response to bacteria resulting in 18-50% mortality) to study how PKC-e protects and understand why the knockout animals are so sensitive to bacteria. The results may improve treatment options for sepsis in humans.
Atherosclerosis: Macrophages are major components of atherosclerotic plaques. Depending on their polarization state, the plaques formed may be stable or vulnerable to rupture leading to heart attack or stroke. We are studying the development of carotid plaques. Using animals that develop either stable or vulnerable plaques, we are defining the immune system to identify biomarkers for risk stratification for stroke. Additionally, we are collaborating with RPI to develop imaging techniques for determination of carotid plaque stability. Such imaging tools will provide clinicians with information that can be used to determine whether a patient requires surgery or medical management. More recently, we have found that animals that develop stable plaques are also protected from the development of fibrotic lung and kidney disease, providing us with an animal model and a clue as to what pathways may contribute to fibrosis.
Cancer: In collaboration with lung oncologists and pathologists, we have determined that the macrophages in lymph nodes positive for lung cancer, are polarized to support tumor cell growth (rather than kill the cells). The ability to “re-educate” these macrophages towards cytotoxicity may open new possibilities for treatment of this deadly type of cancer.
Techniques: Animals models. Real time confocal and TIRF imaging, immunofluorescence of mouse and human tissues, flow cytometry for high throughput analysis of immune status.
Specific projects: 1) identify the function and downstream targets of PKC-e on nascent phagosomes, 2) determine how PKC-e directs the immune response that clears E. coli infection, 3) define the role of Fc receptors in producing stable carotid plaques and preventing fibrotic disease 4) determine the feasibility of combined imaging for detection of unstable human carotid plaques (collaboration with RPI), 5) study the macrophages associated with adenocarcinoma cells in lymph nodes positive for lung cancer (collaboration with pathology and lung oncology). These projects use macrophages and models of human disease to bridge the fields of cell and molecular biology, immunology, and microbiology.
- Harmon, E.Y., Fronhofer, V., Keller, R.S., Feustel, P.J., Zhu, X., Xu, H., Avram, D., Jones D.M., Nagarajan, S., and Lennartz, M.R.: Anti-inflammatory immune skewing is atheroprotective: Apoe-/-FcgammaRIIb-/-mice develop fibrous caretoid plaques. J. Am. Heart Assoc. 3(6). pii.e001232.doi: 10.1161/JAHA.114.001232, 2014.
- Wood, T.R., R.Y. Chow, C.M. Hanes, X. Zhang, K. Kashiwagi, Y. Shirai, M. Trebak, D.J. Loegering, N. Saito, and M.R. Lennartz. 2013. PKC-epsilon pseudosubstrate and catalytic activity are necessary for membrane delivery during IgG-mediated phagocytosis. J. Leukoc. Biol. 94(1):109-122, 2013.
- Harmon, E.Y., V. Fronhofer, R.S. Keller, P.J. Feustel, M.J. Brosnan, J.H. von der Thüsen, D.J. Loegering, and M.R. Lennartz. Ultrasound biomicroscopy for longitudinal studies of carotid plaque development in mice: Validation with histological endpoints. PLoS One 7:e29944, 2012.
- Loegering, D.J. and M.R. Lennartz. Protein kinase C and toll-like receptor signaling. Enzyme Res. 2011:537821, 2011.
- Lennartz, M.R., A. Aggarwal, T.M. Michaud, P.J. Feustel, D.M. Jones, M.J. Brosnan, R.S. Keller, D.J. Loegering, and P.B. Kreienberg. Ligation of macrophage Fc? receptors recapitulates the gene expression pattern of vulnerable human carotid plaques. PLoS ONE 6:e21803, 2011.