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 CD14CD16 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 CD14CD16 monocytes and a need for further investigation into the clinical significance of NRG-1/ERBB signaling as a modulator of immune system function. 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.

Shared genetic and experimental links between obesity-related traits and asthma subtypes in UK Biobank

“…Neuregulin-1/ERBB signaling plays a role in the control of proinflammatory activation of monocytes. 57 Additionally, we found a shared locus (6p21.32, HLA-DRB1-DQA1-DQB1) at the HLA region, which was well-established in playing key roles in the immune system. 58 However, what interests us most was that the shared loci were implemented in cell proliferation, metaplasia, and ECM remodeling, all of which were reported to be important pathology of airway remodeling.…”

Innate Immunity Effector Cells as Inflammatory Drivers of Cardiac Fibrosis

“…In diabetic rats with chronic heart failure, NRG-1 was observed to reverse myocardial interstitial fibrosis [ 159 ]. NRG-1 seems to exert antifibrotic and anti-inflammatory effects acting on macrophages in an ErbB4-mediated manner [ 160 , 161 , 162 ]. After fibrotic stimuli, NRG-1, released from damaged endothelial cells in the endocardium, activates ErB4 and downregulates the PI3K/Akt pathway and the phosphorylation of STAT3 thus reducing the release of proinflammatory mediators such as IL-1β, iNOS, IL-6 and TNF-α ( Figure 2 C).…”

Biomarker discovery in cardiac allograft vasculopathy using targeted aptamer proteomics

“…Erb‐B2 receptor tyrosine kinase 3 (ERBB3) is a peripheral mononuclear cell receptor enzyme and regulator of inflammation . In heart failure patients, lower ERBB3 levels have been correlated with increased pro‐inflammatory cytokines including TNF‐α and IL‐1B and adverse outcomes . Suggesting inflammatory activation, patients with CAV in our study had significantly reduced levels of ERBB3.…”

“…Similarly, the histone cluster 1 H3 family member A (HIST1H3A) protein that is linked to complement and macrophage activation was also elevated in our CAV patients . Erb‐B2 receptor tyrosine kinase 3 (ERBB3) is a peripheral mononuclear cell receptor enzyme and regulator of inflammation . In heart failure patients, lower ERBB3 levels have been correlated with increased pro‐inflammatory cytokines including TNF‐α and IL‐1B and adverse outcomes .…”