Seite - 110 - in Advances in Neuroimmunology

BrainSci. 2017,7, 14 Thepredictedpotential targets ineachgroupweredifferent fromthose inothergroups,both in targetsandtheirpossibilityrankings.VPS28wastheonlyonethatappeared inboth theTop100 lists ofplacebo-control+salineversusplacebo-control+LPS(No. 1 inTable4)andmorphine-tolerant+ salineversusmorphine-tolerant+LPS(No. 4 inTable4). Table4showsthe topthreepotential targetgenes fromeachsetofgenecomparisons. Therewas nosimilarity in thegenerankings in the threesetsofgenecomparisons. Table4. LINCSConsensusKnockdownConnections fromdifferentially expressedgenes in the rat brain in response to lipopolysaccharides (LPS),with andwithoutmorphine tolerance. (A)Top10 ConsensusKnockdownConnections in the three setsofgenecomparisons; (B)Rankingsof the top threeConsensusKnockdownConnections in the three sets of gene comparisons. Full nameof the geneswereprovidedinTableA2. (A) Rank placebo-Salinevs.Placebo-LPS Placebo-Salinevs. Morphine-Tolerant-Saline Morphine-Tolerant-Saline vs.Morphine-Tolerant-LPS 1 VPS28 SMARCE1 AHR 2 PROCR AHRR UBE2L6 3 CHMP2A GPX7 PAFAH1B3 4 MB ATP5F1 VPS28 5 ZNF768 CALR JUNB 6 RBPJ GPR110 RYK 7 WARS2 CHMP2A ARG1 8 TBX2 ELF4 PROC 9 MRPS2 FGFR1 ZNF324 10 MAP3K14 F7 ATP5D (B) GeneRank Placebo-Salinevs.Placebo-LPS Placebo-Salinevs. Morphine-Tolerant-Saline Morphine-Tolerant-Saline vs.Morphine-Tolerant-LPS VPS28 1 42 4 PROCR 2 491 681 CHMP2A 3 7 177 SMARCE1-1 675 1 504 AHRR 2383 2 460 GPX7 488 3 2137 AHR 46 769 1 UBE2L6 89 545 2 PAFAH1B3 95 622 3 4.Discussion Inflammasomesrecognizeavarietyofpathogen-associatedmolecularpatterns(PAMPs), including endotoxinssuchasLPS.DependingontheNLRproteins thatconstitute inflammasomes,aninflamasome canbepro-inflammatoryoranti-inflammatoryinnature[28]. Forpro-inflammatoryinflammasomessuch asNLRP3, invitrostudieshaveshownthat theactivationandreleaseofpro-inflammatorycytokines requirestwosignals.Thefirstsignal, triggeredbyPAMPs,leadstotheactivationofinflammasomes,which thenprovidethesecondsignal. Theactivatedinflammasomes, throughcaspase1activation,promote theproductionof thepro-inflammatorycytokines, IL-1βandIL-18.However, thesignalingpathways duringinfectionor inflammationinvivoarenotyetcompletelydefined[29],andthecharacteristicsof anti-inflammatoryinflammasomessuchasNLRP12havenotyetbeenextensively investigated. Toour knowledge,ourstudyisoneof thefirst toreport themodulationofNLRP12expression inresponse to LPSandmorphine invivo. Recently,NLRP12wasdesignated as an anti-inflammatoryNLR inflammasomeprotein. It is believedtobeanegativeregulatorof theNF-κBsignalingpathwaybyinhibitingdownstreamsignaling ofTLRs,particularly IRAK-1 [28,30]. Our results showedthatNLRP12expressiondecreased in the brainsofboth thecontrol (placebo-control+LPS)andmorphine-tolerant (morphine-tolerant+LPS) rats inresponsetoanLPSchallenge, indicatingthatoneof themechanismsbywhichLPSinducesan inflammatoryresponse isbyinhibitingtheexpressionof theanti-inflammatoryNLRP12inflammasome. Although NLRP12 expression was decreased in both groups given LPS, the decrease was significantlygreater in the control rats than in themorphine-tolerant rats,which suggests that the LPS-inducedNLRP12decrease iscounteredduringmorphinetolerance.Hencemorphinemayalso 110