ERBB signaling attenuates proinflammatory activation of nonclassical monocytes

Sergey Ryzhov, Anton Matafonov, Cristi L. Galindo, Qinkun Zhang, Truc Linh Tran, Daniel J. Lenihan, Carrie Geisberg Lenneman, Igor Feoktistov, Douglas B. Sawyer

    Research output: Contribution to journalArticle

    9 Citations (Scopus)

    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 & NOTEWORTHY This 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.

    Original languageEnglish
    Pages (from-to)H907-H918
    JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
    Volume312
    Issue number5
    DOIs
    Publication statusPublished - 1 May 2017

    Fingerprint

    Neuregulin-1
    Monocytes
    Heart Failure
    Immune System
    Blood Cells
    Systolic Heart Failure
    1-Phosphatidylinositol 4-Kinase
    Protein Isoforms
    Animal Models

    Keywords

    • ERBB receptor tyrosine kinase
    • Heart failure
    • Inflammation
    • Inflammatory

    ASJC Scopus subject areas

    • Physiology
    • Cardiology and Cardiovascular Medicine
    • Physiology (medical)

    Cite this

    Ryzhov, S., Matafonov, A., Galindo, C. L., Zhang, Q., Tran, T. L., Lenihan, D. J., ... Sawyer, D. B. (2017). ERBB signaling attenuates proinflammatory activation of nonclassical monocytes. American Journal of Physiology - Heart and Circulatory Physiology, 312(5), H907-H918. https://doi.org/10.1152/ajpheart.00486.2016

    ERBB signaling attenuates proinflammatory activation of nonclassical monocytes. / Ryzhov, Sergey; Matafonov, Anton; Galindo, Cristi L.; Zhang, Qinkun; Tran, Truc Linh; Lenihan, Daniel J.; Lenneman, Carrie Geisberg; Feoktistov, Igor; Sawyer, Douglas B.

    In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 312, No. 5, 01.05.2017, p. H907-H918.

    Research output: Contribution to journalArticle

    Ryzhov, S, Matafonov, A, Galindo, CL, Zhang, Q, Tran, TL, Lenihan, DJ, Lenneman, CG, Feoktistov, I & Sawyer, DB 2017, 'ERBB signaling attenuates proinflammatory activation of nonclassical monocytes', American Journal of Physiology - Heart and Circulatory Physiology, vol. 312, no. 5, pp. H907-H918. https://doi.org/10.1152/ajpheart.00486.2016
    Ryzhov, Sergey ; Matafonov, Anton ; Galindo, Cristi L. ; Zhang, Qinkun ; Tran, Truc Linh ; Lenihan, Daniel J. ; Lenneman, Carrie Geisberg ; Feoktistov, Igor ; Sawyer, Douglas B. / ERBB signaling attenuates proinflammatory activation of nonclassical monocytes. In: American Journal of Physiology - Heart and Circulatory Physiology. 2017 ; Vol. 312, No. 5. pp. H907-H918.
    @article{e114f3add1b14565b60404f19af314c3,
    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 & NOTEWORTHY This 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.",
    keywords = "ERBB receptor tyrosine kinase, Heart failure, Inflammation, Inflammatory",
    author = "Sergey Ryzhov and Anton Matafonov and Galindo, {Cristi L.} and Qinkun Zhang and Tran, {Truc Linh} and Lenihan, {Daniel J.} and Lenneman, {Carrie Geisberg} and Igor Feoktistov and Sawyer, {Douglas B.}",
    year = "2017",
    month = "5",
    day = "1",
    doi = "10.1152/ajpheart.00486.2016",
    language = "English",
    volume = "312",
    pages = "H907--H918",
    journal = "American Journal of Physiology - Heart and Circulatory Physiology",
    issn = "0363-6135",
    publisher = "American Physiological Society",
    number = "5",

    }

    TY - JOUR

    T1 - ERBB signaling attenuates proinflammatory activation of nonclassical monocytes

    AU - Ryzhov, Sergey

    AU - Matafonov, Anton

    AU - Galindo, Cristi L.

    AU - Zhang, Qinkun

    AU - Tran, Truc Linh

    AU - Lenihan, Daniel J.

    AU - Lenneman, Carrie Geisberg

    AU - Feoktistov, Igor

    AU - Sawyer, Douglas B.

    PY - 2017/5/1

    Y1 - 2017/5/1

    N2 - 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 & NOTEWORTHY This 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.

    AB - 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 & NOTEWORTHY This 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.

    KW - ERBB receptor tyrosine kinase

    KW - Heart failure

    KW - Inflammation

    KW - Inflammatory

    UR - http://www.scopus.com/inward/record.url?scp=85018245614&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=85018245614&partnerID=8YFLogxK

    U2 - 10.1152/ajpheart.00486.2016

    DO - 10.1152/ajpheart.00486.2016

    M3 - Article

    VL - 312

    SP - H907-H918

    JO - American Journal of Physiology - Heart and Circulatory Physiology

    JF - American Journal of Physiology - Heart and Circulatory Physiology

    SN - 0363-6135

    IS - 5

    ER -