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1、Introduction1. Sepsis(败血症) is a life-threatening condition in which bacterial infection occurs in the bloodstream of an individual. This condition is also referred to as systemic inflammatory response syndrome (SIRS-全身性炎症反应综合征). Introduction2. Systemic inflammatory response syndrome(SIRS全身性炎症反应综合征)
2、leads to Multiple organ dysfunction syndrome (MODS多器官功能障碍综合征). Introduction3. Sepsis can be caused due to internal or external infections. Once the microorganisms enter the human body, they have the potential to spread to other parts of the body via blood circulationIntroduction 4. It is commonly th
3、at bacterial endotoxin such as lipopolysaccharide (LPS) causes sepsis. The real mechanism of sepsis lies in the Toll-like receptors that suppress sepsis caused by tissue injury or endotoxin. When Toll-like receptors initial suppression role is overwhelmed, sepsis ensues.LPS TLR4 pathway1.TLR Pathway
4、 is an ancient innate immune systemToll pathways in Drosophila and mammalsLPS TLR4 pathway2. An introduction of LPS2.1 As a component of the gram negative cell envelope, It comprises three parts:1). O antigen (or O polysaccharide)2). Core oligosaccharide3). Lipid A2.2 The lipid A domain is responsib
5、le for much of the toxicity of Gram-negative bacteria.LPS TLR4 pathway3. PAMPs Pathogen associated molecular patterns (LPS)PAMPs are molecules associated with groups of pathogens, that are recognized by cells of the innate immune system. These molecules can be referred to as small molecular motifs c
6、onserved within a class of microbes; therefore microbe-associated molecular pattern,MAMP LPS TLR4 pathway4. PRRs Pattern recognition receptors, are proteins expressed by cells of the innate immune system to identify PAMPs.3.2 The lipid A domain is responsible for much of the toxicity of Gram-negativ
7、e bacteria.Toll Like ReceptorsLPS TLR4 pathway5.Generalized major signal transduction pathway of TLR4 LPS TLR4 pathway6. TLR4 pathway InitiationLPS stimulation of mammalian cells occurs through a series of interactions with several proteins including theLPS binding protein (LBP), CD14, MD-2 and TLR4
8、. LBP is a soluble shuttle protein which directly binds to LPS and facilitates the association between LPS and CD14 . CD14 is a glycosylphosphatidylinositol-anchored protein, which also exists in a soluble form. CD14 facilitates the transfer of LPS to the TLR4/MD-2 receptor complex and modulates LPS
9、 recognition.MD-2 is a soluble protein that non-covalently associates with TLR4 but can directly form a complex with LPS in the absence TLR4. Although no evidence suggests that TLR4 can bind LPS directly, TLR4 can enhance the binding of LPS to MD-2 26. Therefore LPS stimulation of TLR4, includes the
10、 participation of several molecules,and the currently favoured model is outlined. LPS TLR4 pathway7. TLR4 adaptorsUpon LPS recognition, TLR4 undergoes oligomerization and recruits its downstream adaptors through interactions with the TIR (Toll-interleukin-1 receptor) domains.7.1 The MyD88-dependent
11、pathway to be responsible for proinflammatory cytokine expression, 7.2 The MyD88-independent pathwaymediates the induction of Type I interferons and interferon-inducible gene LPS TLR4 pathway8. MyD88-dependent pathway MyD88 death domain recruits IRAK-4IRAK-4 recruits, activates and depredates IRAK-1
12、TRAF6 forms a complex with UBC13 (ubiquitin-conjugating enzyme 13) and UEV1A (ubiquitin-conjugating enzyme E2 variant 1 isoform A), and activates TAK1 (transforming growth factor-activated kinase 1). TAK1 then activates downstream IKK (IB kinase) and MAPK pathways . IKK, IKK and IKK form a complex a
13、nd phosphorylate IB proteins. Then degradation of IB proteins and the subsequent translocation of the transcription factor NF-B, which controls the expression of proinflammatory cytokines, in addition to other immune related genes.LPS TLR4 pathway9. MyD88-independent pathway TRIF plays a key role th
14、e activation of transcription factor IRF3, the late-phase activation of NF- B and MAPK. the deletion of both MyD88 and TRIF leads to severely impaired NF-B and MAPK activation. the induction of Type I interferons was defective in TRAF3-deficient cells.IRF3, together with NF-B, activates the transcription of target genes, such as Type I interferons .LPS TLR4 pathway10. Negative regulation of TLR4 signaling pathwayRP105ST2LTRIAD3ASOCS-1IRAK-MA20Thank you for your attention!