Lipopolysaccharide, Mediator of Sepsis Enigma: Recognition and Signaling

Abstract

The outer leaflet of Gram-negative bacterial membrane contains a great amount of lipopolysaccharides, also known as endotoxins, which play a central role in the pathogenesis of sepsis and ultimately septic shock. Lipopolysaccharide (LPS) is potent inducer of acute sepsis or chronic inflammation. Sepsis can strike anyone, but is most likely to develop from infection associated with events such as pneumonia, trauma, surgery, and burns, or serious illnesses such as cancer and AIDS. In fact, people whose deaths are ascribed to complications of cancer, AIDS, or pneumonia, often actually die as a direct result of sepsis. Sepsis involves a complex interaction between bacterial toxins and the host immune system. LPS stimulates Toll-like receptor (TLR)-4 which leads to the formation and release of range of proinflammatory mediators which are essential for the potent immune response. The massive host response to this single bacterial pattern recognition molecule is sufficient to generate diffuse endothelial injury, tissue hypoperfusion, disseminated intravascular coagulation and refractory shock. LPS recognition involves LPS binding protein (LBP), CD14 ending up in TLR4/MD-2/LPS complex. The complex leads to activation of TLR4 and subsequent signaling cascade via two pathways i. e., myeloid differentiation protein 88 (MyD88)-dependent and TRIF-dependent. Here is a brief review of TLR4 signaling and LPS recognition biology with its impact if any on downstream pathways.