The role of Toll‐like receptor 4 (TLR4) in cardiac ischaemic‐reperfusion injury, cardioprotection and preconditioning

Abstract

Cardiac ischaemic-reperfusion injury (IRI) remains the primary cause of mortality throughout the developed world. Molecular mechanisms underlying IRI are complex and are often interlinked with each other driving a synergistic response. Toll-like receptor 4 (TLR4), an immunosurveillance receptor, is known to enhance tissue injury during IRI by enhancing the inflammatory response. The release of endogenous components during IRI bind onto TLR4 leading to the activation of multiple signalling kinases. Once this event occurs these proteins are defined as danger associated molecular patterns molecules (DAMPs) or alarmins. Examples include heat shock proteins, high mobility group box one (HMGB1) and extracellular matrix proteins, all of which are involved in IRI. However, literature in the last two decades suggests that transient stimulation of TLR4 may suppress IRI and thus improve cardiac recovery. Furthermore, it remains to be seen what role TLR4 plays during ischaemic-preconditioning where acute bouts of ischaemia, preceding a harmful bout of ischaemic-reperfusion, is cardioprotective. The other question which also needs to be considered is that if transient TLR4 signalling drives a preconditioning response then what are the ligands which drive this? Hence the second part of this review explores the possible TLR4 ligands which may promote cardioprotection against IRI.

Transplantation and Damage-Associated Molecular Patterns (DAMPs)

“…Class Ia DAMPs such as HMGB1 and HSPs are generated in reperfusion‐injured organs including human renal allografts , but also emitted under BD conditions . These molecules considerably contribute to creation of sterile inflammation including IRI‐mediated inflammation when sensed by those members of the NLR or ALR family that form inflammasomes .…”

Silencing of Tenascin-C inhibits hypoxia reoxygenation injury of cardiomyocyte through TLR4和NF-κB pathway

“…The present study showed that TNC increased TLR4 expression and promoted NF-κB translocation from cytoplasm to nucleus of cardiomyocytes with H/R injury, which is dependent on IκBα. In response to MI, TLR4 is activated and induce cardiomyocytes express proinflammatory cytokines and initiate a local inflammatory response [6]. TLR4 induced the NF-κB dependent expression of proinflammatory cytokines, such as TNF-α,IL-1β IL-6 [25].…”

“…Toll-like receptor 4 (TLR4) is a primary receptor of the innate immune system and can induce inflammatory response in myocardial ischemia through activating signaling pathways, like nuclear factor kappa B (NF-κB) [6]. Activation of NF-κB promotes production of proinflammatory cytokines, such as interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α) [7].…”

Calcium Ionophore-Induced Extracellular Vesicles Mediate Cytoprotection against Simulated Ischemia/Reperfusion Injury in Cardiomyocyte-Derived Cell Lines by Inducing Heme Oxygenase 1

“…Therefore, TLRs discriminate between “self” and “non-self” and activate the innate immune inflammatory response [ 25 ]. TLRs, mainly TLR2 and TLR4, have been shown to be associated with cardiovascular disease, as well as with cardioprotection afforded by different interventions [ 26 , 27 ]. It is well-documented that inflammation via TLR-mediated MyD88-dependent NF-κB activation plays an important cytoprotective role in myocardial I/R injury [ 28 ], whereas TLR4 is also associated with cardioprotection by the activation of PI3K/Akt signaling, suggesting that there is a crosstalk between TLR and PI3K/Akt pathways in myocardial I/R injury and cardioprotection [ 29 ].…”