Office: 163 Molecular Biosciences, 960 Technology Blvd
Phone: 406 994-4014
Lab: 160 Molecular Biosciences, 960 Technology Blvd
Education and Professional Experience
B.S. Experimental Biology 1983, Åbo Akademi University, Finland
M.S. Experimental Biology 1984, Åbo Akademi University, Finland. Lab of Gun Paatero.
Graduate Studies 1984-85, Microbiology, Helsinki University, Finland
Ph.D. Cell Biology and Experimental Pathology 1990, Yale University, USA. Labs of Ira Mellman and Jack Rose.
Postdoctoral Fellow 1991-1994, Department of Medical Biochemistry, Turku University and Turku Centre for Biotechnology, Finland. Lab of Markku Jalkanen.
Assistant Research Professor, 1994-2004, Department of Microbiology, Montana State University, USA.
Associate Research Professor, 2004-present, Department of Microbiology, Montana State University, USA.
Functional regulation of chemoattractant receptors.
A type of white blood cell called the neutrophil is a key mediator of inflammation. Neutrophils accumulate at sites of bacterial infection because they can sense the presence of, and migrate toward, various molecules called chemoattractants. Key chemoattractants include formylated peptides that are released from bacteria, and the C5a fragment that is produced upon activation of the complement cascade. Neutrophils have specific receptors for these two ligands, the formyl peptide receptor 1 (FPR1) and the C5a receptor (C5aR; CD88). FPR1 and C5aR belong to a large family of G protein-coupled receptors (GPCRs) that transmit their signal from the outside to the inside of the cell through a heterotrimeric G protein (Gi). In addition to their anti-microbial role, neutrophils have been implicated in the pathogenesis of a variety of chronic inflammatory disorders, such as rheumatoid arthritis, Crohn’s disease and systemic lupus erythematosus. In addition, neutrophils can cause major tissue damage in atherosclerosis, asthma, and ischemia-reperfusion injury. In these diseases, neutrophils and other surrounding cells stimulate one another in a perpetuating, unregulated loop. It is therefore of great importance to increase our understanding of the functional regulation of neutrophils.
Recently, we have focused our attention on the regulation of FPR1 and C5aR expression. We have characterized in detail the transcriptional regulation of FPR1 by mapping the promoter region, identifying transcription factors, and examining the role of inflammatory mediators. The results suggest that FPR1 is fully expressed in mature neutrophils and does not get further up-regulated during inflammation. Thus, it is unlikely that therapeutic targeting using FPR1 siRNA would be beneficial, whereas specific antagonists would likely aid in the resolution of inflammation mediated by FPR1. In contrast, our studies suggest that inflammatory mediators up-regulate C5aR expression. In addition, several studies show profound reduction of inflammation in various disease models through inhibition of C5a binding to C5aR. Our goal is to develop strategies to target only destructive C5aR-expressing cells, such as neutrophils and inflammatory monocytes without affecting other C5aR-bearing cells and tissues. First, we will examine the reduction in C5aR expression through gene silencing and through targeting of specific transcription factors. Thereafter, we will investigate ways to target the inflammatory pool of cells by taking advantage of surface molecules that are expressed at high numbers in these cells. These approaches may eventually result in faster resolution of inflammatory disorders.
Publications (selected from last 13 years):
1. Miettinen, H. M., Mills, J. S., Gripentrog, J. M., Dratz, E. A., Granger, B. L., and Jesaitis, A. J. (1997). The ligand binding site of the formyl peptide receptor maps in the transmembrane region. Journal of Immunology. 159, 4045-4054. Link: pdf
2. Mills, J. S., Miettinen, H. M., Barnidge, D., Vlases, M. J., Wimer-Mackin, S., Dratz, E. A., Sunner, J., and Jesaitis, A. J. (1998). Identification of a ligand binding site in the human neutrophil formyl peptide receptor using a site-specific fluorescent photoaffinity label and mass spectrometry. Journal of Biological Chemistry, 273, 10428-10435. Link: pdf
3. Miettinen, H. M., Gripentrog, J. M., and Jesaitis, A. J. (1998). Chemotaxis of Chinese hamster ovary cells expressing the human neutrophil formyl peptide receptor: Role of signal transduction molecules and ∝5β1 integrin. Journal of Cell Science, 111, 1921-1928. Link: pdf
4. Edens, H. A., Parkos, C. A., Liang, T. W., Jesaitis, A. J., Cutler, J. E., and Miettinen, H. M. (1999). Non-serum-dependent chemotactic factors produced by Candida albicans stimulate chemotaxis by binding to the formyl peptide receptor on neutrophils and to an unknown receptor on macrophages. Infection and Immunity, 67, 1063-1071. Link: pdf
5. Miettinen, H. M., Gripentrog, J. M., Mason, M. M., and Jesaitis, A. J. (1999). Identification of putative sites of interaction between the human formyl peptide receptor and G protein. Journal of Biological Chemistry, 274, 27934-27942. Link: pdf
6. Mills, J. S., Miettinen, H. M., Vlases, M., and Jesaitis, A. J. (1999). “The N-formyl Peptide Receptor: Structure, Signaling, and Disease” In: Molecular Biology of Inflammation. Edited by. Serhan, C. N. and Ward, P. A. pages 215-245. Humana Press.
7. Gripentrog, J. M., Jesaitis, A. J., and Miettinen, H. M. (2000). A single amino acid substitution (N297A) in the conserved NPXXY sequence of the human N-formyl peptide receptor results in inhibition of desensitization and endocytosis and a dose-dependent shift in p42/44 MAPK activation and chemotaxis. Biochemical Journal, 352, 399-407. Link: pdf
8. Mills, J. S., Miettinen, H. M., Cummings, D., and Jesaitis, A. J. (2000). Characterization of the binding site on the formyl peptide receptor using three receptor mutants and analogs of Met-Leu-Phe and Met-Met-Trp-Leu-Leu. Journal of Biological Chemistry, 275, 39012-39017. Link: pdf
9. Grimes, M. L. and Miettinen, H. M. (2003). Receptor tyrosine kinase and G protein-coupled receptor signaling and sorting within endosomes. Journal of Neurochemistry, 84, 905-918. Link: pdf
10. Gripentrog, J. M., Kantele, K. P., Jesaitis, A. J. and Miettinen, H. M. (2003). Experimental evidence for lack of homodimerization of the G protein-coupled human N-formyl peptide receptor. Journal of Immunology, 171, 3187-3193. Link: pdf
11. Suvorova, E. S., Gripentrog, J. M., and Miettinen, H. M. (2005). Different endocytosis pathways of the C5a receptor and the N-formyl peptide receptor. Traffic, 6, 100-115. Link: pdf
12. Gripentrog, J. M., and Miettinen, H. M. (2005). Activation and nuclear translocation of ERK1/2 by the formyl peptide receptor is regulated by G protein and is not dependent on β-arrestin translocation or receptor endocytosis. Cellular Signalling, 17, 1300-1311. Link: pdf
14. Gripentrog, J. M., and Miettinen, H. M. (2008). Formyl peptide receptor-mediated ERK1/2 activation occurs through Gi and is not dependent on ß-arrestin1/2. Cellular Signalling, 20, 424-431. Link: pdf
15. Gripentrog, J. M., Mills, J. S., Saari, G. J., and Miettinen, H. M. (2008). Variable responses of formyl peptide receptor haplotypes toward bacterial peptides. Immunogenetics., 60, 83-93. Link: pdf
16. Suvorova, E. S., Gripentrog, J. M., Oppermann, M., and Miettinen, H. M. (2008). Role of the carboxyl terminal di-leucine in phosphorylation and internalization of C5a receptor. Biochim. Biophys. Acta-Mol. Cell Res., 1783, 1261-1270. Link: pdf
17. Suvorova, E. S., Gripentrog, J. M., Jesaitis, A.J., and Miettinen, H. M. (2009). Agonist-dependent phosphorylation of the formyl peptide receptor is regulated by the membrane proximal region of the cytoplasmic tail. Biochim. Biophys. Acta-Mol. Cell Res., 1793, 406-417. Link: pdf
18. Miettinen, H. M. (2011), Regulation of human formyl peptide receptor 1 synthesis: Role of single nucleotide polymorphisms, transcription factors, and inflammatory mediators. PLoS ONE 6(12), e28712 Link: pdf
The links, opinions or statements expressed herein should not be taken as a position or endorsement of MSU-Bozeman or its affiliates.