Page - 135 - in Advances in Neuroimmunology

BrainSci. 2017,7, 11 4.4. Cellular ImmuneResponse toTBI Several reports show thatTBI and the associatedneuroinflammation lead to local deposition of specific immune cells at the peri-injury area and beyond [97,114,115]. In addition, peripheral inflammation can also influence TBI outcomes [116]. There appears to be a rapid expansion and activationofperipheral immunecellsafterexperimentalTBI,aswellasasignificantextravasationof immunecells fromthespleen, resultinginsplenichypotrophyfollowingTBI[117,118]. It isalsoknown that someof these immunecells thatexit thespleencancontribute to the innate immuneresponse, andsomemayalsocontribute toanensuingadaptive immuneresponse followingaTBI [116,119,120]. Similarly, it isalsoknownthatsomeof these immunecellswill infiltrate theCNS[121–123]. Immune cells involvedincoordinatingthe innate immuneresponse include: (1)monocytes,whichdevelop into macrophages; (2)mastcells; (3)granulocytes (basophils, eosinophilsandneutrophils); (4)dendritic cells (DC);and(5)naturalkillercells. Neutrophilsandmacrophagesstrongly infiltrate thebrain in theearlyphaseofTBI [121,123,124]. Neutrophils appear to be themost numerous type of granulocytes and possess high phagocytic potential. These cells are highlymigratory andwere reported to be involved in phagocytosing damagedelementswithin thebrainparenchymafollowingaTBI [115,122]. Theprocesseswhereby neutrophils functionareby: (1) secreting lysosomalenzymes; (2) releasingfreeradicals; (3)decreasing bloodflowbydirectphysicalmicrovascularocclusion; (4) increasingvascularpermeability [125–127]. Interestingly, neutrophils canbe found in themicrovasculature lining theperi-injury regionbyas earlyas2hafter injuryandinbrainparenchymashortly thereafter [115,122]. Thus,neutrophilscan contribute to thedevelopmentofBBBbreakdownandsubsequentbrainedemaformation[122,128]. It ispossible thatneutrophilscontribute to thesecondarydamageseenafterTBI.Consistentwith this notion,blockingneutrophilmigrationandadhesiondecreases the totalareaofneuronaldamageafter aTBI inrabbits [129]. IthasbeenhypothesizedthataccumulationofDCsat thesiteofdamagedbrainparenchymacan negatively contribute tobrain tissuedamageafter theonset ofTBI [122,130]. InfiltratingDCsmay beactivatedbycontactwith thedamagedcellsat thesiteof injury.Antigenmaterialsgetprocessed byDCs,whichcanthantravel todistant lymphnodes,presentantigenandgeneratea local immune response.Once this response is initiated,antigen-specificTcellsmaymigrate intoCNSparenchyma andcauseextended, chronicdamageto thebrain [131,132]. Tcell accumulationat thesiteof injury, concurrentwithDCaccumulation,hasalsobeen indicatedtonegatively influenceTBIoutcomes [115]. Activatedmacrophagesand/ormicrogliaalsocontribute toneuronaldamage[122,133]. Ithas been reported that different molecules released after TBI contribute to microglia/macrophage phenotype shifts [134,135]. Although the utility of classifying theM1/M2phenotype invivo has comeintoquestion[136,137], it is stilluseful toreviewthepotential impactof thedifferentphenotypes. For example, damagedendothelial cells canmediatemicroglia/macrophagepolarization through secretionof cytokines [138], such asTNF-α, IL-6, IL-25, transforminggrowth factor beta (TGF-β), interferon-gamma (IFN-gamma), including substance-P and lipocalin-2 [139–141]. Additionally, infiltratingperipheral immunecells (T lymphocytesspecifically)can inducemacrophage/microglial phenotype transformation [142]. Recent studies suggest that such phenotype changes can alter neurogenesisafterTBI,suchthatmacrophagepolarizationfromM2towardM1stimulatesthereleaseof soluble factors that impairbasalneurogenesis [138], andthismayimpair functional recovery [134,143]. Thus,macrophagesand/ormicroglial cells canbeacteduponbyanumberof factors thatultimately determine the functionalconsequencesof thesecell types. Macrophages, including both resident (microglia) and infiltrating (peripheralmacrophages), areobserved inrelativelyhighnumbers followingTBIs [133].Macrophagesappearedtobeabundant between12and72handpredominate indamagedcortical regions [122,144]. Thesecellsaccumulate near the areaof injury [144], and this accumulation is a result of at least twomechanisms. One is throughattractionsbylocally-secretedchemo-andcytokinesreleasedat thesiteof injury,aspreviously discussed. Theothermechanismappears to occurvia theT-cell activation. Once in thedamaged 135