PGN-TLR2 Up-regulation Of RAGE Promotes Macrophage Pyroptosis

BACKGROUNDSevere peritonitis-induced sepsis is controlled by clearance of peritoneal bacteria by macrophages and neutrophils during the early phases of sepsis.Severe peritonitis-induced sepsis and ensuing multiple organ dysfunction syndrome with septic shock continue to be clinical critical disease.Based on the latest epidemiological survey,about 750 000 cases of severe sepsis per year occur in the USA alone,with an annual mortality estimated at 210 000.The mortality rate for sepsis is above 20%,Sepsis is still the leading cause of death in clinic,a rate higher than that of heart disease.Despite advancement in modern medicine and a better understanding of the pathophysiology of sepsis,there are no specific therapeutic interventions for the treatment of sepsis.Sepsis remains the most challenging problem inclinic.Sepsis is a life-threatening illness that refers to an abnormal host immune response against invading pathogen,which extends through the initial uncontrolled and overwhelming systemic inflammation and culminates at the late stage of prolonged immune suppression.Recently,Immune suppression and inflammation are the two most highly focused areas of active investigation concerning pathogenesis in sepsis.In the early phase of sepsis,pathogenic microorganisms stimulate the host to release large amounts of pro-inflammatory cytokines,leading to the development of severe inflammatory response syndrome.SIRS most likely emerges in infection due to pathogen-associated molecular patterns(PAMPs)interacting with toll-like receptors activate immune system.PGN as a very important PAMP is expressed on both G+and G-,play a vital role in sepsis.In the pathogenesis of sepsis,pathogen components(e.g.,PGN)are potent activators to trigger inflammatory responses via interacting with toll-like receptors 2.The innate immune system can also be activated by damage-associated molecular pattern(DAMP)molecules.As we known,high mobility group box 1(HMGB1)is involved in sepsis,which contribute to the recruitment of leukocyte and subsequent organ damage.The activation of immune reactive cells is responsible for the elimination of bacteria.However,the ovewhelming response of the immune system with an excessive release of inflammatory mediators,suggests an inability to regulate the immune response,which could result in immunesupression in the late stages of sepsis.Sepsis-induced immunosuppressive state is characterized by impared pathogen clearance,immune cells apoptosis,enhanced necrosis of cells,the profound loss of immune reactive cells as well as the induction of tolerance,which eventually exaggerated response of the inflammation.Macrophages,are the first-line to fight against sepsis,owning variable phenotypes and diverse functions,were becoming the target cells in inflammatory,infectious and autoimmune diseases.RAGE is expressed in a variety of cell types,including macrophages.RAGE has been implicated in mediating the cytokine activity of HMGB1.Study reports that HMGB1 seems to act as a late mediator involved in pathophysiology of sepsis.RAGE knockout mice were recently reported to be resistant to septic shock induced by cecal ligation and puncture,suggesting that RAGE potentially plays a role in sepsis.Pyroptosis is a new way of newly discovered cell death.Pytoptotic cell death in macrophages may contribute to amply inflammation involved in sepsis.Pyroptosis is a caspase-1 dependent programmed cell death,which features rapid plasma membrane rupture,DNA fragmentation,chromatin condensation,and results in the lysis of cell and release of cytosolic contents.Similar to oncosis,and unlike apoptosis,pyroptosis results in cellular lysis and release of the cytosolic conents to the extracellular space.NLRP3 inflammasome activation,which can activate caspase-1,causing pyroptosis.CONCLUSIONOur study demonstrated that the TLR2 dependent RAGE upregulation in Mcp is significantly augmented by PGN;the upregulated RAGE induces the formation of inflammasome and pyroptosome in response to RAGE ligand(HMGB1),sequentialy leads to caspase-1 activation and aguments pyroptosis formation.What is more,when the pyrototic macrophages were cocultured with normal macrophages,the cytokines was elevated.Suggests that the pyroptotic cells exaggerate inflammation by influence neiburgh cells.In turn,exaggerate inflammatory response,and promote the development of sepsis.