Toll-like receptor signaling during myocardial ischemia.

A CUTE myocardial infarction and myocardial ischemia are leading causes of shortand long-term morbidity and mortality in the perioperative period. In part, this relates to the fact that treatment options for a myocardial infarction in surgical patients are extremely limited. For example, anticoagulation or treatment with highly effective inhibitors of platelet aggregation may not be an option due to the risk for bleeding from the operative site. Therefore, it is not surprising that the search for new pharmacologic approaches to treat myocardial ischemia or to render the myocardium more resistant to limited oxygen availability is an area of intense investigation for perioperative scientists. In fact, the introduction of intraoperative -blockers for cardioprotection from ischemia was one of the most significant alterations in anesthesia practice during the past 15 y. In line with the search for novel therapeutic approaches to render the myocardium more resistant to ischemia, a very exciting research study by Wang et al., from the research laboratory of Dr. Wei Chao from the Anesthesia Center for Critical Care Research of the Massachusetts General Hospital in Boston, provides new insight into signaling pathways involving toll-like receptor (TLR)-elicited cardioprotection from ischemia. TLRs are named after the German word “toll,” which carries the meaning of “great” or “amazing.” In fact, a team of scientists led by Dr. Christiane Nüsslein-Volhard, Ph.D. (Professor, Max Planck Institute, Tübingen, Germany) identified Toll as a gene critical in the embryogenesis of fruit flies by establishing the dorsal-ventral axis of Drosophila. The name derives from Christiane Nüsslein-Volhard’s 1985 exclamation, “Das war ja toll,” which translates as “that’s amazing,” in reference to the underdeveloped ventral portion of a fruit fly larva. Together with Edward B. Lewis and Eric Wieschaus, she received the Nobel Prize in Physiology or Medicine in 1995 for her discoveries concerning the genetic control of early embryonic development. Ten years after the original discovery of the Toll gene, a novel role for Toll beyond its function in embryogenesis was discovered. In fact, mutant flies deficient in Toll were more susceptible to fungal or bacterial infections. In 1997, a group of scientists from Yale University led by Ruslan Medzhitov (Professor, Yale University School of Medicine, New Haven, CT) and Charles Janeway Jr. (Professor, Yale University School of Medicine, New Haven, CT) (1943–2003) described a human homolog of the Drosophila Toll protein that had the resemblance of a cytoplasmatic receptor (“Toll-like”). In this landmark study, human Toll was identified as a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor. Moreover, constitutively active mutant of human Toll transfected into human cell lines could induce the activation of nuclear factor (NF) B and the expression of NF B-target genes. As such, today’s view of “Toll-like receptors” has evolved toward a class of receptor proteins that play a key role in the innate immune system. They are single-membrane–spanning, noncatalytic receptors that recognize structurally conserved molecules derived from microbes (pattern recognition receptors). For example, studies of mice deficient in TLR4—the key TLR for the recognition of lipopolysaccharide—show hyporesponsiveness to lipopolysaccharide treatment. Currently, 10 TLR family members have been described in human. They differ in their specificity for different microbial compounds. For example TLR2 can be activated by lipoteichoic acid from Gram-positive bacteria, TLR4 by lipopolysaccharide from Gram-negative bacteria, or TLR5 by flagellin, the filament of bacterial flagella found on most motile bacteria. Activation of TLRs involves specific signal transduction pathways, including myeloid differentiation factor 88 (MyD88)or TIR–domain-containing adaptor protein-inducing interferon–mediated transcription factor (Trif)-dependent (MyD88-independent) pathways that culminate in the activation of NF B, thus promoting a pro-inflammatory host program. TLR signaling has been implicated in many forms of inflammatory disorders in human. For instance, a cosegregating missense mutation (Asp299Gly and Thr399Ile) affecting the extracellular domain of the TLR4 receptor is associated with a blunted response to inhaled lipopolysaccharide in humans. This common Asp299Gly polymorphism of TLR4 also predicts low concentrations of circulating inflammatory mediators and confers an increased risk of severe infections but carries a reduced risk of atherosclerosis in human. Although TLR signaling has been extensively studied in the context of innate immunity, other studies have also implicated TLR signaling in noninfectious tissue injury, such as occurs in the context of myocardial infarction. As such, the studies by Wang et al. build on the observation that previous administration of a small, nonlethal dose of the TLR4 agonist lipopolysaccharide results in robust cardioprotection from subsequent myocardial ischemia–reperfusion injury. To gain mechanistic insight on how TLR4 activation confers cardioprotection from