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

Summary 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 ( TLR 4), 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 TLR 4 leading to the activation of multiple signalling kinases. Once this event occurs these proteins are defined as danger associated molecular patterns molecules ( DAMP s) or alarmins. Examples include heat shock proteins, high mobility group box one ( HMGB 1) and extracellular matrix proteins, all of which are involved in IRI . However, literature in the last two decades suggests that transient stimulation of TLR 4 may suppress IRI and thus improve cardiac recovery. Furthermore, it remains to be seen what role TLR 4 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 TLR 4 signalling drives a preconditioning response then what are the ligands which drive this? Hence the second part of this review explores the possible TLR 4 ligands which may promote cardioprotection against IRI .