Abstract
Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that modulate innate immune responses and play essential roles in the pathogenesis of heart diseases. Although important, the molecular mechanisms controlling cardiac TLR genes expression have not been clearly addressed. This study examined the expression pattern of Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, Tlr8, and Tlr9 in normal and disease-stressed mouse hearts. Our results demonstrated that the expression levels of cardiac Tlr3, Tlr7, Tlr8, and Tlr9 increased with age between neonatal and adult developmental stages, whereas the expression of Tlr5 decreased with age. Furthermore, pathological stress increased the expression levels of Tlr2, Tlr4, Tlr5, Tlr7, Tlr8, and Tlr9. Hippo-YAP signaling is essential for heart development and homeostasis maintenance, and YAP/TEAD1 complex is the terminal effector of this pathway. Here we found that TEAD1 directly bound genomic regions adjacent to Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, and Tlr9. In vitro, luciferase reporter data suggest that YAP/TEAD1 repression of Tlr4 depends on a conserved TEAD1 binding motif near Tlr4 transcription start site. In vivo, cardiomyocyte-specific YAP depletion increased the expression of most examined TLR genes, activated the synthesis of pro-inflammatory cytokines, and predisposed the heart to lipopolysaccharide stress. In conclusion, our data indicate that the expression of cardiac TLR genes is associated with age and activated by pathological stress and suggest that YAP/TEAD1 complex is a default repressor of cardiac TLR genes.
Highlights
Heart failure is one of the leading causes of mortality and morbidity in the developed countries [1]
Toll-like receptors (TLRs) genes are expressed in both cardiomyocytes (CMs) and non-CMs [4], and disturbance of TLR genes expression has been implicated in a range of heart diseases, including pathogen and non-pathogen related heart failure [5,6]
We have recently reported that cardiomyocyte-specific YAP depletion up-regulated Tlr2 and Tlr4 [16]; it is unknown whether YAP directly regulates these two TLR genes through TEAD1 and whether YAP/TEAD1 complex regulates other TLR genes
Summary
Heart failure is one of the leading causes of mortality and morbidity in the developed countries [1]. Involved in the pathogenesis of heart failure, Toll-like receptors (TLR) are a family of pattern recognition receptors that sense pathogenic stimuli and signal the cardiac residential cells to cope with harsh conditions [2]. Human and mouse genomes contain 10 (TLR1–10) and 13 (Tlr1–13) TLR genes, respectively. Tlr, and Tlr exist in mouse but not in the human genome, and murine Tlr is a pseudogene [3]. Despite the importance of TLR genes in the pathogenesis of heart failure, the molecular mechanisms that regulate these genes’ expression are largely unknown
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