After stimulating macrophages with a small dose of lipopolysaccharide (LPS) for the first time, when they are stimulated again with a larger dose of endotoxin, the secretion of cytokines and the toxic effect are weakened or even unresponsive, so that the body can resist the lethal effect of endotoxin, which is called endotoxin tolerance (ET). Endotoxin tolerance includes natural endotoxin tolerance and induced endotoxin tolerance. The phenomenon of artificially induced ET can only be maintained under certain conditions, and once the specific conditions are removed, ET will disappear. Natural ET is associated with mutations in some signaling molecules. The emergence of ET in host cells requires a process of gene expression reprogramming, which also involves increased expression of anti-inflammatory mediators. ET, as the body's protective mechanism against inflammation, can improve symptoms such as fever, hypoxia, and shock. Repeated or constant exposure to LPS will reduce the secretion of certain active mediators in the body, which is beneficial to patients with sepsis. However, the specific mechanism of the formation of endotoxin resistance is still not very clear. Recently, there have been many studies on the molecular mechanism of ET, mainly focusing on the receptors interacting with LPS and the cell signal transduction pathways behind the receptors.
The molecular basis of ET includes the involvement of many downstream molecules of LPS signal transduction, the most important of which is the TLR4 molecule. One of the major molecular mechanisms for host immune cells to detect Gram-negative pathogens and their endotoxins is ET signaling via the TLR4 pathway. TLR4 is one of the most important families of Toll-like receptors (TLRs), which plays a key role in initiating innate immune responses and promoting adaptive immune responses. As a transmembrane receptor on the LPS target cell membrane, TLR4 mainly mediates transmembrane transduction of LPS signals, changes in the structure and function of TLR4, and various links in the TLR4 signaling pathway (MD2, MyD88, IRAK, IκB, NF-κB). When inflammation cytokines fail to function, LPS resistance can be produced. Taken together, TLR4 plays an important role in the pathogenesis of endotoxin resistance.
Figure 1. TLR4 Signaling pathway. (Firmal P, et al., 2020)
According to reports, ET is not only seen in infectious diseases such as sepsis and SIRS pancreatitis but also in non-infectious diseases such as trauma, diabetes, hepatic ischemia-reperfusion injury, cystic fibrosis, and cancer. Sepsis is a systemic inflammatory response syndrome caused by infection. A major hallmark of ET during sepsis is the inability of monocytes/macrophages to step up adaptive responses, which may be responsible for poor evolution during sepsis. In the state of ET, blood monocytes from sepsis patients express high levels of PD-L1 on their cell surface through the induction of HIF1, and control of the induction of T cell proliferation during ET is impaired. To sum up, ET is a protective regulatory mechanism formed in the long-term evolution of organisms. In clinical application, it plays a significant role in preventing damage caused by excessive response to ET stimulation by the body.
ET is a complex pathophysiological process involving multiple cell signaling pathways, receptor changes, and biomolecules, and is a protective mechanism produced by the body against excessive inflammatory responses. At the same time, it is related to the secondary infection of various diseases and the mortality rate of patients. A better understanding of the protective and regulatory mechanisms of ET has important inspiration and value for the clinical treatment of various related diseases.
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