Page - 94 - in Advances in Neuroimmunology

BrainSci. 2016,6, 25 4hafter stress exposure in controls, correspondingcytokineproteinswerenot alteredat this time point ineitherS–DorWistarRats (Table1).Neuroimmuneresponses toWCEsometimes followed the response to stress and sometimesdidnot. WhileCCL2, TNFα, IL-1β, andTLR4 responses in the cortexweregenerally comparablyhighwitheither challenge, responses in theamygdalawere comparablyminimal.However, in thehippocampus, responsesvariedbytypeofchallengeandacross neuroimmunemarkerswitharobustCCL2response towithdrawalandacomparable IL-1β response toeitherchallenge. In thehypothalamus, stresswas inactivewhilewithdrawalelevatedCCL2and IL-1β. Finally, theresultsshowedthatCRF1Rinhibitiondidnotalterstress-inducedneuroimmune responses in thecortex,aresult inconsistentwith theearlierfindings thatCRF1Rinhibitionblocked cytokineresponses tochronicwithdrawal [38]. Thereasonthatstress increasedselect cytokinemRNAsbutnotcorrespondingcytokineproteins isunknown. ThispatternofmRNAversusprotein results is similar to that observed in studies in otherareasof ratbrain. Forexample,Huestonetal. [21]demonstratedan increase in IL-1βmRNA withoutanaccompanying increase in IL-1βprotein in theparaventricularnucleus (PVN)torestraint stress.Deaketal. [19] foundthat IL-1βproteindidnot increase in thehypothalamusofS–Dratsafter restraint stressalonebutdidobservean increase in IL-1β tostress in thehypothalamusafterapplying acombinationofrestraintandshaking(i.e., amoreseverestress).Additionally,Porterfieldetal. [39] foundthat2hof restraint increasedexpressionof IL-1βmRNAinthehypothalamusandcauseda correspondingincreaseinthiscytokineproteininthemorestress-responsiveFischer344rats,butnot in S–Drats [39].However,Whitmanetal. [38] foundthatanacuteLPSchallenge increasedbothselected cytokineproteinsandcorrespondingcytokinemRNAsin thecortexofS–Drats [38].Whilea focuson thehypothalamusandIL-1 (e.g., [19,23])hasbeenafruitful focusofprior researchso farasconsistent effects of stress are concerned, reports of combinationsof stressorsmaybeparticularlyworthyof followup. Inaddition to theworkofDeaketal. [19]andPorterfieldetal. [39]notedabove,priorcold stress renderedanimals’neuroimmunesystemsresponsive to futureLPS treatment [20], as shown byelevatedhypothalamicandprefrontal corticalneuroimmunemarkers).Consideredinaggregate, suchstudiessuggestthatgeneticbackgroundand/orthedegreeandcombinationsofstressorchallenge to theneuroimmunesystemmaybeat least inpart responsible for thepresenceofaneuroimmune responseandpossiblyfordifferences inproteinversusmRNAresponsesaswell. Itmaybeparticularly interesting in thiscontext toexamine thepossibility thatdifferentiallyengagedmolecularmechanisms ofmRNAversus protein processing across timemay account for asynchrony of these constructs. That is, theobservationof a stress-associated increase in cytokinemRNAswithout corresponding changes incytokineproteinscouldalsobeexplainedbyrelease,utilization,anddegradationof the proteinduringthestresschallenge.Relatedly,habituationorexhaustionofmRNAgenerationcould alsobeafactor insomecases. Inthiscontext,Minamietal. [23]showedthat theIL-1βmRNAresponse in the hypothalamusdeclined over four hours despite continued immobilization stress. Such an effect could conceivablyhave influencedouramygdala andhypothalamicfindings, butwouldbe harder toextendtoourcorticalandhippocampalresults.Alsorelevant is themorerecent reportof Vecchiarellietal. [26]whofoundthat increasingthelengthofrestraintstress inSprague–Dawleyrats to twohourselevatedprotein levelsofamygdalaTNFα,decreasedIL-6,whilemonocytechemoattractant protein-1 (MCP-1/CCL2) remained unchanged. Based on our data, it is unlikely that any such diminished cortical response would apply to the cortex globally. Differential responses across subregions of the cortexmight be criticalwith the net effect of global cortical responses being an increasedresponse thatmustbedependentonsomeregion(s)beingparticularlysensitive. Extending this logic to thehippocampusorhypothalamusmaybepremature,asVecchiarellididnotseechanges in these regions. The singlehourof restraint stress in thepresentworkdidnot alter amygdalaor hypothalamicTNFαmRNAbutdid increasecortical IL-1β,TNFαandCCL2,andhippocampal IL-1β. Perhaps the length or severity of stress, alongwith a focus on cortical subregions represent key prerequisites toexaminationsof either individualor combinatorial challenges. Further research to 94