Research in our lab is directed toward understanding the function of two neutrophil receptors, the formyl peptide receptor 1 (FPR1) and the C5a receptor (C5aR; CD88), which play a central role in inflammation. Ligand binding to these receptors leads to important host defense functions such as killing of microorganisms. Unfortunately, neutrophils are also involved in the pathology of various inflammatory conditions. Our goal is to learn more about neutrophil activation by studying the functions of FPR1 and C5aR. 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 result in faster resolution of inflammation in cases such as atherosclerosis, ischemia-reperfusion injury, and autoimmune disorders.
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.
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 b-arrestin translocation or receptor endocytosis. Cell. Signal. 17, 1300-1311.
Riesselman, M., Miettinen, H. M., Gripentrog, J. M., Lord, C. I., Mumey, B., Dratz, E. A., Taylor, R. M., and Jesaitis, A. J. (2007). N-formyl peptide receptor C-terminal tail phosphorylation in the specific granule pool and after fMLF activation: Differential receptor recognition by monoclonal antibodies NFPR1 and NFPR2. J. Immunol. 179, 2520-2531.
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. Cell. Signal. 20, 424-431.
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.
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. Biophy. Acta - Mol. Cell Res. 1783, 1261-1270.
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. Biophy. Acta - Mol. Cell Res., 1793, 406-417.
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. doi:10.1371/journal.pone.0028712.