ERBB signaling attenuates pro-inflammatory activation of non-classical monocytes

Immune activation in chronic systolic heart failure (HF) correlates with disease severity and prognosis. Recombinant neuregulin-1 (NRG-1) is being developed as a possible therapy for HF based on 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 the recombinant NRG-1 isoform glial growth factor 2 (GGF2) in subpopulations of peripheral blood mononuclear cells in subjects with HF. We found that human monocytes express both ERBB2 and ERBB3 receptors, with high inter-individual variability among subjects. Monocyte surface ERBB3 and TNFα 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 TNFα production specifically in CD14 low CD16+ population of monocytes in a PI-3-kinase dependent manner. GGF2 suppression of TNFα correlated directly with the expression of ERBB3. In vivo, a single dose of intravenous GGF2 reduced TNFα expression in peripheral blood mononuclear cells of HF subjects participating in a Phase I safety study of GGF2. These results support a role for ERBB3 signaling in regulation of TNFα 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.