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

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    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

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    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., Lenneman, C. G., Feoktistov, I., & 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