Michelle R. Lennartz, PhD
Areas of Study
Cell biology of macrophages
- University of Michigan School of Medicine1984PhD
Macrophages play a major role in health and disease. They recognize and destroy 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) and cell migration/metastasis.
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 studying the intracellular signaling pathways that prevent macrophages from effectively clearing bacteria.
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.
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. Current efforts are focused on understanding how antibodies can tune macrophages to be pro-inflammatory (to recognize and kill tumor cells) or pro-resolution (to promote tumor progression).
Animals models. Real time confocal and TIRF imaging, immunofluorescence of mouse and human tissues, flow cytometry for high throughput analysis of immune status.
1) identify the function and downstream targets of PKC-e on nascent phagosomes,
2) determine how PKC-e expression levels promote or protect against the development of atherosclerosis,
3) understand how antibodies can elicit pro-inflammatory AND pro-resolution responses from macrophages, and how those responses can be tuned therapeutically, and
4) determine how PKC-e acts to promote directional migration and how tumor cells utilize PKC-e for that migration. These projects use macrophages and models of human disease to bridge the fields of cell and cancer biology, immunology, and microbiology.
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.
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.
View Michelle R. Lennartz's articles on the National Institute of Health's PubMed website.