INDIVIDUAL RESEARCHERMichelle R. Lennartz , Ph.D.
Education1984 - Ph.D. from University of Michigan, 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 are a reservoir for a select group of pathogens, including HIV, Mycobacterium tuberculosis (the causative agent of TB), and Francisella tularensis (a category A biodefense organism). 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 that results in stroke and heart attack. More recently, we have begun using a mouse model of tularemia to understand how F. tularensis invades macrophages and proliferates within them. We use real time imaging to follow uptake of particles (pathogens or IgG-coated particles) and the movement of signaling molecules during this process. We have identified Protein Kinase C-µ as a critical mediator of phagocytosis and phospholipase D as its upstream activator. Understanding the mechanism of PKC-µ activation and determining its downstream targets are active areas of investigation. Using viral vectors to deliver signaling molecules to macrophages, we are also studying the pathways linking the IgG receptor to gene activation. The genes of interest are the matrix metalloproteinases that contribute to plaque rupture, thrombosis and stroke. Finally, F. tularensis is a pathogen that preferentially infects macrophages, including those in the lung that can be accessed by inhalation. Although it is a category A biodefense pathogen, capable of being weaponized, little is known about how it invades and survives within the macrophage. We are using a mouse model of this pathogen (non-infectious to humans) to study how it is taken up and traffics within macrophages to understand why it can thrive within the normally hostile environment of the macrophage. Techniques being used include immunofluorescence, electron microscopy, and confocal imaging. Specific projects include: 1) identifying the regions of PKC-µ responsible for membrane localization and the membrane molecules to which they dock, 2) identifying the downstream targets of activated PKC-µ, 3) determining the signal transduction pathway leading to production of matrix metalloproteinases by macrophages enzymes, 4) defining the receptors responsible for internalization of F. tularensis by macrophages, and 5) identifying the macrophage organelles which support F. tularensis growth. These projects use macrophages to bridge the fields of cell and molecular biology, immunology, microbiology, and biodefense.
- Lennartz MR. (1999) Phospholipases and phagocytosis: the role of the phospholipid-derived second messengers in phagocytosis. Int J Biochem Cell Biol 31:415-430.
- Karimi K, Gemmill T, and Lennartz MR. (1999) Protein kinase C and a calcium-independent phospholipase are required for IgG-mediated phagocytosis by mono mac 6 cells. J Leukocyte Biol 65:854-862.
- Larsen EC, DiGennaro JA, Saito N, Mehta S, Loegering DJ, Mazurkiewicz JE, and Lennartz MR. (2000) Differential requirement for classic and novel PKC isoforms in respiratory burst and phagocytosis in RAW 264.7 cells. J Immunol 165:2809-2817.
- Larsen EC, Ueyama T, Brannock PM, Shirai Y, Saito N, Larsson C, Loegering DJ, Weber PB, and Lennartz MR. (2002) A role for PKC-µ in Fc³R-mediated phagocytosis by RAW 264.7 cells. J Cell Biol 159:939-944.