title: ERBB signaling attenuates proinflammatory activation of nonclassical monocytes.
abstract: Immune activation in chronic systolic heart failure (HF) correlates with disease severity and prognosis. Recombinant neuregulin-1 (rNRG-1) is being developed as a possible therapy for HF, based on the activation of ERBB receptors in cardiac cells. Work in animal models of HF led us to hypothesize that there may be direct effects of NRG-1 on immune system activation and inflammation. We investigated the expression of ERBB receptors and the effect of rNRG-1 isoform glial growth factor 2 (GGF2) in subpopulations of peripheral blood mononuclear cells (PB MNCs) in subjects with HF. We found that human monocytes express both ERBB2 and ERBB3 receptors, with high interindividual variability among subjects. Monocyte surface ERBB3 and TNF-α mRNA expression were inversely correlated in subjects with HF but not in human subjects without HF. GGF2 activation of ERBB signaling ex vivo inhibited LPS-induced TNF-α production, specifically in the CD14lowCD16+population of monocytes in a phosphoinositide 3-kinase-dependent manner. GGF2 suppression of TNF-α correlated directly with the expression of ERBB3. In vivo, a single dose of intravenous GGF2 reduced TNF-α expression in PB MNCs of HF subjects participating in a phase I safety study of GGF2. These results support a role for ERBB3 signaling in the regulation of TNF-α production from CD14lowCD16+monocytes and a need for further investigation into the clinical significance of NRG-1/ERBB signaling as a modulator of immune system function.NEW & NOTEWORTHYThis study identified a novel role of neuregulin-1 (NRG-1)/ERBB signaling in the control of proinflammatory activation of monocytes. These results further improve our fundamental understanding of cardioprotective effects of NRG-1 in patients with heart failure.
authors.affiliation: Maine Medical Center Research Institute, Scarborough, Maine.
authors.forename: Sergey
authors.initials: S
authors.lastname: Ryzhov
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee.|Department of Bioengineering and Organic Chemistry, Tomsk Polytechnic University, Tomsk, Russia.
authors.forename: Anton
authors.initials: A
authors.lastname: Matafonov
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Cristi L
authors.initials: CL
authors.lastname: Galindo
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Qinkun
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Truc-Linh
authors.initials: TL
authors.lastname: Tran
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lenihan
authors.affiliation: University of Louisville, Louisville, Kentucky; and.
authors.forename: Carrie Geisberg
authors.initials: CG
authors.lastname: Lenneman
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Igor
authors.initials: I
authors.lastname: Feoktistov
authors.affiliation: Maine Medical Center Research Institute, Scarborough, Maine; DSawyer@mmc.org.|Maine Medical Center, Portland, Maine.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Sawyer
mesh_terms: D066246:ErbB Receptors / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000503:physiopathology*; D008262:Macrophage Activation; D008297:Male; D008875:Middle Aged; D009000:Monocytes; D020890:Neuregulin-1 / Q000378:metabolism / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D020893:Receptor, ErbB-3 / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D066246:ErbB Receptors; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C094131:NRG1 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: ERBB receptor tyrosine kinase; heart failure; inflammation; inflammatory cytokine; neuregulin