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., 2005; Lee et al., 2004; Pang et al., 2001) Interestingly, when CVE expressionof VCAM-1 is intact, but astrocytic expression is selectively lost, T cells accumu-late perivascularly but do not penetrate into the CNS parenchyma (Gimenez et al.,2004) suggesting that astrocytic expression of adhesion molecules is crucial for thepenetration of leukocytes into the CNS parenchyma.Microglia can also expresshigh levels of adhesion molecules after stimulation via TLRs, although it isunknown how they contribute to leukocyte invasion (Dalpke et al., 2002; Olson andMiller, 2004).Glial cells are also sources of cytokines that may impact developing adaptiveimmune responses in the CNS.Stimulation of astrocytes with flagellin, PGN,LPS, CpG, or poly I:C is effective in inducing IL-6, IL-1 and TNF production, thecytokines most frequently expressed by activated astrocytes (Bowman et al., 2003;Carpentier et al., 2005; Esen et al., 2004; Farina et al., 2005; Sharif et al., 1993;Takeshita et al., 2001).These cytokines are also produced by astrocytes in vivoduring neuroinflammation (Maimone et al., 1997; Sun et al., 1995).Microgliaalso express TNF, IL-6, and IL-1² in response to the TLR agonists LPS, poly I:C, PGN and CpG DNA (Kielian et al., 2002; Lee et al., 1993; Olson and Miller,2004; Takeshita et al., 2001).All of these molecules have the potential to activatea pro-inflammatory response in the both the CNS and the periphery and have alsobeen implicated in mediating BBB damage (de Vries et al., 1996) and promotingefficient leukocyte entry into the CNS.Microglia in vitro produce IL-12, IL-18,and IL-23, potent cytokines involved in Th1 differentiation, in response to manyof these stimuli (Constantinescu et al., 1996; Dalpke et al., 2002; Li et al., 2003;Olson and Miller, 2004; Stalder et al., 1997; Takeshita et al., 2001).Astrocyteshave been reported to express these molecules as well (Constantinescu et al.,1996, 2005; Stalder et al., 1997), although it is generally thought that microgliaare the major CNS resident source of IL-12 and IL-23 (Wheeler and Owens,2005).The complete roles of cytokines during CNS inflammation is discussedelsewhere in this volume. Pattern Recognition Receptors in CNS Disease 137TLR stimuli also promote the phagocytic activity of microglia which becomebactericidal upon stimulation with CpG DNA, E.coli DNA, and S.aureus in vitro(Dalpke et al., 2002; Kielian et al., 2002).Increased phagocytic activity promotes theprocessing of antigens for presentation to T cells.Upon LPS, poly I:C, or CpG DNAstimulation, murine microglia upregulate cell surface expression of both costimula-tory molecules and MHC I and II, which are critical for T cell activation (Dalpkeet al., 2002; Kielian et al., 2002; Olson and Miller, 2004).Microglia become capableof processing and presenting antigen to CD4+ and CD8+ T cells following TLR ligandand IFN-³ exposure, indicating microglia may be relevant for activating CD4+ andCD8+ T cells infiltrating the CNS (Dalpke et al., 2002; Dhib-Jalbut et al., 1990; Freiet al., 1987; McMahon et al., 2005; Olson and Miller, 2004).Although PAMPs are efficient at inducing innate immune functions of astro-cytes, they are not effective at inducing antigen presenting cell functions ofastrocytes (Carpentier et al., 2005).LPS or poly I:C stimulated astrocytes are notable to efficiently activate CD4+ T cells due to a deficiency of MHC class IIexpression, indicating that astrocytes are likely not involved in activation of T cellsinfiltrating the CNS early after infection.In contrast, astrocytes constitutivelyexpress low levels of MHC I which is increased by poly I:C stimulation or virusinfection and these cells can therefore possibly activate or be lysed by CD8+ Tcells (Carpentier et al., 2007; Cornet et al., 2000; Suzumura et al., 1986).Several investigators have confirmed the necessity of TLRs for responses of glial cellsto these ligands as well as to pathogens.As expected, CD14 and TLR4 are required forglial responses to LPS (Kitamura et al., 2001; Qin et al., 2005).Similarly, TLR3 is neces-sary for full glial activation by poly I:C (Park et al., 2006; So et al., 2006; Town et al.,2006) and TLR2 mediates glial responses to PGN (Esen et al., 2004; Kielian et al.,2005a).Interestingly, TLR2 also mediates astrocyte responses to intact S.aureus, but itis dispensable for microglial activation by the same bacteria (Esen et al., 2004; Kielianet al., 2005a), indicating that microglia, but not astrocytes, have multiple mechanisms bywhich recognition of this bacteria occurs.We have also noted that while TLR3-/- astro-cytes display reduced responses to poly I:C, their responses to direct infection withTheiler s virus are normal.Rather, it appears that PKR is the more important mediator ofinflammation in virus-infected astrocytes (Carpentier et al., 2007).It is not surprising thatresponses to intact pathogens do not depend on a single TLR, but rather multiple path-ways can be activated and compensate for loss or lack of another.Such redundancy isnecessary for protective immunity, since so many pathogens have evolved mechanismsto block innate immune signaling pathways as a mechanism of immune evasion.3.2 CNS Cells are Activated by PeripherallyAdministered PAMPsIt has long been recognized that peripheral infection has profound effects in theCNS, resulting in fever and stimulation of the hypothalamic-pituitary-adrenal axis.Peripheral infection or injection of LPS also causes a set of behavioral symptoms 138 P.A.Carpentier et al.collectively termed sickness behavior , including anorexia, modification of sleeppatterns, decreased locomotor activity, libido, social and exploratory behavior (Rothet al., 2004).Peripheral injection of LPS results in a variety of molecular changes inthe CNS, particularly the upregulation of pro-inflammatory cytokines like IL-6, IL-1²,and TNF, (Breder et al., 1994; Chakravarty and Herkenham, 2005; Vallieres andRivest, 1997).Many of these effects can be mimicked by the intravenous injection ofhigh levels of the recombinant cytokines, and blocking cytokine action in the periph-ery or CNS can partially inhibit the induction of fever and sickness behavior (Rothet al., 2004), suggesting that many of the infection-induced CNS effects result fromthe production of pro-inflammatory cytokines by peripheral immune cells.However,cytokine-targeting strategies to prevent LPS-induced fever are only partially effective,and the early response to LPS is often intact (Roth et al., 1998), indicating that othermechanisms must also be involved.The CNS response to pyrogens is thought to beinitiated in the CVOs, which lack a blood brain barrier and therefore are accessibleto large circulating molecules.CVOs express high levels of TLR4 and CD14 in com-parison to the rest of the CNS parenchyma (Chakravarty and Herkenham, 2005;Laflamme and Rivest, 2001), demonstrating the possibility that these organs candirectly respond to circulating LPS
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