ERBB signaling attenuates proinflammatory activation of nonclassical monocytes

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 312; no. 5; pp. H907 - H918
• Main Authors: Ryzhov, Sergey, Matafonov, Anton, Galindo, Cristi L., Zhang, Qinkun, Tran, Truc-Linh, Lenihan, Daniel J., Lenneman, Carrie Geisberg, Feoktistov, Igor, Sawyer, Douglas B.
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.05.2017
• Series: Integrative Cardiovascular Physiology and Pathophysiology
• Subjects: Activation; Cells; Correlation; Correlation analysis; ErbB Receptors - biosynthesis; ErbB Receptors - drug effects; ErbB Receptors - genetics; Female; Gene expression; Growth factors; Heart failure; Humans; Immune system; In Vitro Techniques; Inflammation - physiopathology; Kinases; Macrophage Activation; Male; Middle Aged; Monocytes; Neuregulin-1 - metabolism; Neuregulin-1 - therapeutic use; Phosphatidylinositol 3-Kinases - metabolism; Receptor, ErbB-2 - biosynthesis; Receptor, ErbB-2 - genetics; Receptor, ErbB-3 - biosynthesis; Receptor, ErbB-3 - genetics; Receptors; Recombinant Proteins - metabolism; Ribonucleic acid; RNA; Signal Transduction; Signaling; Tumor Necrosis Factor-alpha - biosynthesis; neuregulin; heart failure; inflammatory cytokine; inflammation; ERBB receptor tyrosine kinase
• ISSN: 0363-6135; 1522-1539; 1522-1539
• DOI: 10.1152/ajpheart.00486.2016

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 CD14 low CD16 + 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 CD14 low CD16 + 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.