Toll-like receptor-2 in cardiomyocytes and macrophages mediates isoproterenol-induced cardiac inflammation and remodeling.

Abstract

Heart failure (HF) is the leading cause of morbidity and mortality worldwide. Activation of the innate immune system initiates an inflammatory response during cardiac remodeling induced by isoproterenol (ISO). Here, we investigated whether Toll-like receptor-2 (TLR2) mediates ISO-induced inflammation, hypertrophy, and fibrosis. TLR2 was found to be increased in the heart tissues of mouse with HF under ISO challenge. Further, cardiomyocytes and macrophages were identified as the main cellular sources of the increased TLR2 levels in the model under ISO stimulation. The effect of TLR2 deficiency on ISO-induced cardiac remodeling was determined using TLR2 knockout mice and bone marrow transplantation models. In vitro studies involving ISO-treated cultured cardiomyocytes and macrophages showed that TLR2 knockdown significantly decreased ISO-induced cell inflammation and remodeling via MAPKs/NF-κB signaling. Mechanistically, ISO significantly increased the TLR2-MyD88 interaction in the above cells in a TLR1-dependent manner. Finally, DAMPs, such as HSP70 and fibronectin 1 (FN1), were found to be released from the cells under ISO stimulation, which further activated TLR1/2-Myd88 signaling and subsequently activated pro-inflammatory cytokine expression and cardiac remodeling. In summary, our findings suggest that TLR2 may be a target for the alleviation of chronic adrenergic stimulation-associated HF. In addition, this paper points out the possibility of TLR2 as a new target for heart failure under ISO stimulation.