Network Topologies and Dynamics Leading to Endotoxin Tolerance and Priming in Innate Immune Cells 英文参考文献.docVIP
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Network Topologies and Dynamics Leading to Endotoxin Tolerance and Priming in Innate Immune Cells 英文参考文献
NetworkTopologiesandDynamicsLeadingtoEndotoxin
ToleranceandPriminginInnateImmuneCells
YanFu1,2,TrevorGlaros1,MengZhu3,PingWang1,ZhanghanWu1,2,JohnJ.Tyson1,LiwuLi1*,
JianhuaXing1*
1DepartmentofBiologicalSciences,VirginiaPolytechnicInstituteandStateUniversity,Blacksburg,Virginia,UnitedStatesofAmerica,2InterdisciplinaryPhDProgramof
Genetics, Bioinformatics and Computational Biology, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America, 3School of
Computing,ClemsonUniversity,Clemson,SouthCarolina,UnitedStatesofAmerica
Abstract
The innate immune system, acting as the first line of host defense, senses and adapts to foreign challenges through
complex intracellular and intercellular signaling networks. Endotoxin tolerance and priming elicited by macrophages are
classic examples of the complex adaptation of innate immune cells. Upon repetitive exposures to different doses of
bacterial endotoxin (lipopolysaccharide) or other stimulants, macrophages show either suppressed or augmented
inflammatory responses compared to a single exposure to the stimulant. Endotoxin tolerance and priming are critically
involved in both immune homeostasis and the pathogenesis of diverse inflammatory diseases. However, the underlying
molecular mechanismsarenotwellunderstood. Bymeans ofacomputational searchthrough theparameter space ofa
coarse-grained three-node network with a two-stage Metropolis sampling approach, we enumerated all the network
topologiesthatcangenerateprimingortolerance.Wediscoveredthreemajormechanismsforpriming(pathwaysynergy,
suppressor deactivation, activatorinduction) andone for tolerance (inhibitor persistence). These results not onlyexplain
existing experimental observations, but also reveal intriguing test scenarios for future experimental studies to clarify
mechanismsofendotoxinprimingandtolerance.
Citation:FuY,GlarosT,ZhuM,WangP,WuZ,etal.(2012)NetworkTopologiesandDynamicsLeadingtoEndotoxinToleranceandPriminginInnateIm
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