Thrombin engages neutrophil-derived secretion products to upregulate interleukin-6 production in atrial cardiomyocytes and the heart

Abstract Interleukin-6 (IL-6) exerts a highly context-dependent influence on cardiac injury and repair, inflammation and resolution. Thrombin is a dichotomous regulator of these processes in the post-infarcted heart via protease-activated receptors (PAR), particularly neutrophil-expressed PAR4 Cardiomyocytes are an intrinsic source of myocardial IL-6, but it is not known if this can be triggered by thrombin. Here we examined IL-6 production in cardiomyocytes and how this relates to cardiomyocyte-neutrophil cross-talk in the presence of thrombin. In HL-1 cardiomyocytes, thrombin failed to regulate IL-6 expression and secretion, unlike oxidized albumin (oxAlb), an advanced oxidation protein product (AOPP) recognized by CD36 scavenger receptors. Thrombin, however, increased myeloperoxidase (MPO) release and formation of AOPP by human neutrophils in autologous plasma. HL-1 cardiomyocytes exposed to conditioned supernatant from thrombin-stimulated versus control neutrophils displayed higher levels of IL-6 mRNA and greater IL-6 secretion, an effect largely abrogated in the presence of a CD36 inhibitor. In mice with high fat diet (HFD)-induced obesity and cardiometabolic inflammation, myocardial MPO activity and AOPP content were elevated compared to chow-fed mice, together with higher expression of CD36 and IL-6. In conclusion, thrombin evokes neutrophil-dependent oxidation of plasma proteins that can promote cardiomyocyte IL-6 production, likely promoting local inflammation in cardiometabolic disease.