The Role of Toll-Like Receptor Signaling in the Progression of Heart Failure

Figure 1

Activation of TLRs in heart cells by PAMPs and DAMPs during heart failure. Heart cells express a variety of TLRs, mainly, TLR2, TLR3, TLR4, and TLR9. DAMP and PAMP molecules, which include endotoxin, HSP60, HMGB1, ROS, TNC, lipoproteins, virus RNA, and mtDNA, are involved in HF. Lipoproteins have been reported to activate TLR2. Endotoxin, HSP60, HMGB1, ROS, and TNC have been demonstrated to activate TLR4. dsRNA can be recognized by TLR3. TLR9 can recognize mtDNA to induce immune responses. There are two pathways for TLR signaling, including the Myd88-dependent and Myd88-independent signaling pathways. TLR2 and TLR9 utilize the Myd88-dependent pathway. TLR3 uses the Myd88-independent pathway. TLR4 employs both Myd88 and TRIF as adaptor proteins. Note that TLR3 and TLR9 are predominately located within endosomes. In the Myd88-dependent signaling pathway, stimulation of TLR triggers association of My88, which in turn recruits the IRAK family, and subsequently, TRAF6 is also recruited to the receptor complex by associating with phosphorylated IRAKs. Ubiquitylation of TRAF6 induces the activation of TAK1, which phosphorylates both MAPK kinases and the IKK complex consisting of IKK-α, IKK-β, and IKK-γ. The IKK complex then phosphorylates IκB, which is then ubiquitylated and subsequently degraded. This result allows NF-κB to translocate to the nucleus and induce the expression of its target genes. TRIF play an essential role in the Myd88-independent pathway through TLR3 and TLR4. TRIF interacts with TRAF6, which activates TBK1 and IKK-ε for phosphorylation of the transcription factor IRFs. TRIF can also promote NF-κB activation. TRIF recruits TRAF6 and activates TAK1, which in turn activates the NF-κB and MAPK pathways. These signaling pathways result in the expression of cytokines. Inflammation induces cell injury and death, resulting in cardiac dysfunction and HF progression.