TLR2 Mediates Proliferation and Survival of Cardiomyocytes in Response to Injury

Neonatal, unlike adult hearts, can regenerate and adapt to stress. To identify both cardioprotective and regenerative mechanisms, we compared activated genes and related signalling pathways in the neonatal mouse heart, after myocardial infarction (MI), and exposure to pressure overload by a neonatal model of transverse aortic constriction (nTAC) at postnatal day 1 (P1). We identified three immune-related genes—Ccl4, S100a8, and C1qa—of high interest, as these encode secreted factors, are highly expressed in the neonatal mouse heart in both injury types, and express receptors on cardiomyocytes (CM) and endothelial cells (EC). We investigated their effects on primary mouse cardiac EC and CM in vitro . Our study revealed that the combination of these secreted factors (Pool3) enhances EC and CM proliferation and reduces apoptosis rates. Combined in vivo and in vitro transcriptome analyses revealed that TLR2 activation in CM induces a shared pro-survival and pro-proliferative signalling, including upregulation of Bcl-2. The direct and pivotal role of TLR2 in enhancing CM proliferation and survival was further confirmed using either TLR2 knockout CM, a TLR2 blocking antibody, or a TLR2 agonist (zymosan). Thus, we showed that TLR2 on CM is critical in mediating CM proliferation and survival (Figure 1).