DAMPs Released from Proinflammatory Macrophages Induce Inflammation in Cardiomyocytes via Activation of TLR4 and TNFR

Cardiac dysfunction is a life-threatening complication in sepsis. Upon infection and cardiac stress, the cardiac macrophage population expands. Recruited macrophages exhibit a predominantly proinflammatory phenotype and release danger-associated molecular patterns (DAMPs) that contribute to cardiac dysfunction. However, the underlying pathomechanisms are highly complex and not fully understood. Here, we utilized an indirect macrophage-cardiomyocyte co-culture model to study the effects of proinflammatory macrophages on the activation of different cardiac receptors (TLR3, TLR4, and TNFR) and their role in cardiac inflammation and caspase-3/7 activation. The stimulation of cardiomyocytes with conditioned medium of LPS-stimulated macrophages resulted in elevated IL-6 protein concentrations and relative IL-6 and TNF alpha mRNA levels. Conditioned medium from LPS-stimulated macrophages also induced NF kappa B translocation and increased caspase-3/7 activation in cardiomyocytes. Analyzing the role of different cardiac receptors, we found that TLR4 and TNFR inhibition reduces cardiac inflammation and that the inhibition of TNFR prevents NF kappa B translocation into the nuclei of cardiomyocytes, induced by exposure to conditioned medium of proinflammatory macrophages. Moreover, we demonstrated that TLR3 inhibition reduces macrophage-mediated caspase-3/7 activation. Our results suggest that the immune response of macrophages under inflammatory conditions leads to the release of DAMPs, such as eRNA and cytokines, which in turn induce cardiomyocyte dysfunction. Thus, the data obtained in this study contribute to a better understanding of the pathophysiological mechanisms of cardiac dysfunction.

Automated summary

Cardiac dysfunction is a life-threatening complication in sepsis. Proinflammatory macrophages activate different cardiac receptors and induce cardiac inflammation and caspase-3/7 activation. Inhibition of TLR4 and TNFR reduces cardiac inflammation, while inhibition of TNFR prevents NF kappa B translocation into the nuclei of cardiomyocytes. Inhibition of TLR3 reduces macrophage-mediated caspase-3/7 activation.