Role of genetic variation in FPR1 for monocyte responses to formyl peptide receptor activation
Examensarbete för masterexamen
Biotechnology (MPBIO), MSc
Formyl peptide receptors (FPRs) belong to the class of seven transmembrane G-protein-coupled receptors (GPCRs) and are involved in a wide range of physiological and biological processes including cellular differentiation, defense against microorganisms, inflammation and wound healing. FPRs are therefore conceivable targets in drug development. The most studied aspect of FPRs is arguably their role in innate immunity. FPRs expressed by leukocytes thus detect N-terminal formylated peptides that are released by invading bacteria. This interaction results in chemotaxis to facilitate migration of immune cells to the site of infection along with the formation of pro-inflammatory cytokines and reactive oxygen species (ROS), formed by the NOX2 enzyme, from myeloid leukocytes. Experimental studies of FPR function often utilize short peptides such as fMLF and WKYMVm that ligate FPRs (“FPR agonists”) and thus trigger these inflammatory events in leukocytes. There is variation in the human genes encoding FPRs, but the impact of the genetic variation on the function of FPRs is largely unknown. A main objective of this study therefore was to clarify whether or not single nucleotide polymorphisms (SNPs) in FPR1 may determine the responsiveness of a subset of human myeloid cells (monocytes) to FPR agonists with special reference to differentiation, chemotaxis and ROS formation. The results imply that these monocyte functions are induced by ligation of FPR independently of genetic variation in FPR1. However, the kinetics of ROS formation and elimination after exposure to FPR agonists was distinctly altered in subjects carrying a minor allele SNP in FPR1. The study also comprised studies on the in vivo and in vitro effects of a NOX2 inhibitor, histamine dihydrochloride (HDC) on FPR expression by myeloid cells. The results suggest that HDC up-regulates the expression of FPR1 and FPR2 in vitro but not when administered to experimental animals in vivo.
Farmakologi och toxikologi , Cell- och molekylärbiologi , Medicinsk bioteknologi (med inriktning mot cellbiologi) , Livsvetenskaper , Pharmacology and Toxicology , Cell and Molecular Biology , Medical Biotechnology (with a focus on Cell Biology) , Life Science