Activation of ERBB3 Receptor Prevents TNFα Production from Human Non‐Classical Monocytes

Abstract

Immune cells amplify the progression of chronic heart failure (CHF). Recombinant neuregulin‐1 (NRG1) represents a potential therapy for the treatment of various forms of heart failure. We hypothesized that NRG1, acting via ERBB receptors, inhibits pro‐inflammatory cell activation in CHF. Using flow cytometry, we found that peripheral blood monocytes (PBMs) represent a major subpopulation of mononuclear cells expressing both ERBB2 and ERBB3 receptors. A strong inverse correlation was found between expression of ERBB3 and TNFa mRNA in PBMs from patients with heart failure (rs=‐0.682, p=0.001) but not in control subjects (rs=‐0.042, p=0.886). To determine direct effects of ERBB3 signaling on activation of PBMs we used a model of LPS‐induced TNFa production in ex vivo short‐term culture of PBMs. We found that glial growth factor 2(GGF2; USAN ‐ cimaglermin alfa), NRG1 isoform type II, decreased LPS‐induced TNFa production in CD14lowCD16+ non‐classical monocytes. The inhibitory effect of GGF2 on LPS‐induced TNFa production in CD14lowCD16+ monocytes strongly correlated with the expression of ERBB3 (rs=0.769, p=0.013). In contrast to non‐classical PBMs, we found no effect of GGF2 in CD14highCD16‐ subset of classical monocytes irrespective of their expression of ERBB3. Taken together, our results suggest that ERBB3 signaling plays an important role in inhibition of TNFa production from CD14lowCD16+ cells. Given that non‐classical monocytes play a central role in initiation of vascular inflammation, the stimulation of ERBB3 signaling in these cells may potentially slow progression of CHF.