title: RhoA/ROCK downregulates FPR2-mediated NADPH oxidase activation in mouse bone marrow granulocytes.
abstract: Polymorphonuclear neutrophils (PMNs) express the high and low affinity receptors to formylated peptides (mFPR1 and mFPR2 in mice, accordingly). RhoA/ROCK (Rho activated kinase) pathway is crucial for cell motility and oxidase activity regulated via FPRs. There are contradictory data on RhoA-mediated regulation of NADPH oxidase activity in phagocytes. We have shown divergent Rho GTPases signaling via mFPR1 and mFPR2 to NADPH oxidase in PMNs from inflammatory site. The present study was aimed to find out the role of RhoA/ROCK in the respiratory burst activated via mFPR1 and mFPR2 in the bone marrow PMNs. Different kinetics of RhoA activation were detected with 0.1μM fMLF and 1μM WKYMVM operating via mFPR1 and mFPR2, accordingly. RhoA was translocated in fMLF-activated cells towards the cell center and juxtamembrane space versus uniform allocation in the resting cells. Specific inhibition of RhoA by CT04, Rho inhibitor I, weakly depressed the respiratory burst induced via mFPR1, but significantly increased the one induced via mFPR2. Inhibition of ROCK, the main effector of RhoA, by Y27632 led to the same effect on the respiratory burst. Regulation of mFPR2-induced respiratory response by ROCK was impossible under the cytoskeleton disruption by cytochalasin D, whereas it persisted in the case of mFPR1 activation. Thus we suggest RhoA to be one of the regulatory and signal transduction components in the respiratory burst through FPRs in the mouse bone marrow PMNs. Both mFPR1 and mFPR2 binding with a ligand trigger the activation of RhoA. FPR1 signaling through RhoA/ROCK increases NADPH-oxidase activity. But in FPR2 action RhoA/ROCK together with cytoskeleton-linked systems down-regulates NADPH-oxidase. This mechanism could restrain the reactive oxygen species dependent damage of own tissues during the chemotaxis of PMNs and in the resting cells.
authors.affiliation: Kazan State Medical Academy, 11 Moushtary St, 420012 Kazan, Russian Federation. Electronic address: julia.v.filina@gmail.com.
authors.forename: Julia V
authors.initials: JV
authors.lastname: Filina
authors.affiliation: Kazan State Medical Academy, 11 Moushtary St, 420012 Kazan, Russian Federation. Electronic address: aida.gabdoulkhakova@gmail.com.
authors.forename: Aida G
authors.initials: AG
authors.lastname: Gabdoulkhakova
authors.affiliation: Institute of Cell Biophysics, Russian Academy of Sciences, 3 Institutskaya St, 142290, Pushchino, Russian Federation. Electronic address: safronova@icb.psn.ru.
authors.forename: Valentina G
authors.initials: VG
authors.lastname: Safronova
mesh_terms: D000577:Amides / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D015536:Down-Regulation / Q000187:drug effects; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D019255:NADPH Oxidases / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D044042:Receptors, Formyl Peptide / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein
chemical_list: D000577:Amides; D010455:Peptides; D011725:Pyridines; D044042:Receptors, Formyl Peptide; C481578:formyl peptide receptor 2, mouse; C108830:Y 27632; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019255:NADPH Oxidases; D054460:rho-Associated Kinases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: Formylpeptide receptor signaling; Granulocyte; Respiratory burst; Rho/ROCK