Long Term Potentiation Is Impaired in Membrane Glycoprotein CD200-deficient Mice

The membrane glycoprotein CD200 is expressed on several cell types, including neurons, whereas expression of its receptor, CD200R, is restricted principally to cells of the myeloid lineage, including microglia. The interaction between CD200 and CD200R maintains microglia and macrophages in a quiescent state; therefore, CD200-deficient mice express an inflammatory phenotype exhibiting increased macrophage or microglial activation in models of arthritis, encephalitis, and uveoretinitis. Here, we report that lipopolysaccharide (LPS) and Pam3CysSerLys4 exerted more profound effects on release of the proinflammatory cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNFα), in glia prepared from CD200−/− mice compared with wild type mice. This effect is explained by the loss of CD200 on astrocytes, which modulates microglial activation. Expression of Toll-like receptors 4 and 2 (TLR4 and -2) was increased in glia prepared from CD200−/− mice, and the evidence indicates that microglial activation, assessed by the increased numbers of CD11b+ cells that stained positively for both MHCII and CD40, was enhanced in CD200−/− mice compared with wild type mice. These neuroinflammatory changes were associated with impaired long term potentiation (LTP) in CA1 of hippocampal slices prepared from CD200−/− mice. One possible explanation for this is the increase in TNFα in hippocampal tissue prepared from CD200−/− mice because TNFα application inhibited LTP in CA1. Significantly, LPS and Pam3CysSerLys4, at concentrations that did not affect LTP in wild type mice, inhibited LTP in slices prepared from CD200−/− mice, probably due to the accompanying increase in TLR2 and TLR4. Thus, the neuroinflammatory changes that result from CD200 deficiency have a negative impact on synaptic plasticity. The membrane glycoprotein CD200 is expressed on several cell types, including neurons, whereas expression of its receptor, CD200R, is restricted principally to cells of the myeloid lineage, including microglia. The interaction between CD200 and CD200R maintains microglia and macrophages in a quiescent state; therefore, CD200-deficient mice express an inflammatory phenotype exhibiting increased macrophage or microglial activation in models of arthritis, encephalitis, and uveoretinitis. Here, we report that lipopolysaccharide (LPS) and Pam3CysSerLys4 exerted more profound effects on release of the proinflammatory cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNFα), in glia prepared from CD200−/− mice compared with wild type mice. This effect is explained by the loss of CD200 on astrocytes, which modulates microglial activation. Expression of Toll-like receptors 4 and 2 (TLR4 and -2) was increased in glia prepared from CD200−/− mice, and the evidence indicates that microglial activation, assessed by the increased numbers of CD11b+ cells that stained positively for both MHCII and CD40, was enhanced in CD200−/− mice compared with wild type mice. These neuroinflammatory changes were associated with impaired long term potentiation (LTP) in CA1 of hippocampal slices prepared from CD200−/− mice. One possible explanation for this is the increase in TNFα in hippocampal tissue prepared from CD200−/− mice because TNFα application inhibited LTP in CA1. Significantly, LPS and Pam3CysSerLys4, at concentrations that did not affect LTP in wild type mice, inhibited LTP in slices prepared from CD200−/− mice, probably due to the accompanying increase in TLR2 and TLR4. Thus, the neuroinflammatory changes that result from CD200 deficiency have a negative impact on synaptic plasticity. IntroductionCD200 is a type-1 membrane glycoprotein which has been identified as an immunosuppressive molecule, consistent with its expression on cells of the immune system, including dendritic cells, T and B cells, and endothelial and epithelial cells (1Barclay A.N. Immunology. 1981; 44: 727-736PubMed Google Scholar). Diverse immunomodulatory roles for CD200 have been reported; these include antigen-specific T cell responses, suppression of regulatory T cells (2Pallasch C.P. Ulbrich S. Brinker R. Hallek M. Uger R.A. Wendtner C.M. Leuk. Res. 2009; 33: 460-464Crossref PubMed Scopus (58) Google Scholar), cytotoxic T cell-mediated tumor suppression (3Siva A. Xin H. Qin F. Oltean D. Bowdish K.S. Kretz-Rommel A. Cancer Immunol. Immunother. 2008; 57: 987-996Crossref PubMed Scopus (74) Google Scholar), graft survival (4Gorczynski R.M. Yu K. Clark D. J. Immunol. 2000; 165: 4854-4860Crossref PubMed Scopus (65) Google Scholar), and apoptosis-associated immune tolerance (5Rosenblum M.D. Olasz E. Woodliff J.E. Johnson B.D. Konkol M.C. Gerber K.A. Orentas R.J. Sandford G. Truitt R.L. Blood. 2004; 103: 2691-2698Crossref PubMed Scopus (66) Google Scholar).In the brain, CD200 is expressed on neurons (6Barclay A.N. Wright G.J. Brooke G. Brown M.H. Trends Immunol. 2002; 23: 285-290Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar) and oligodendrocytes (7Koning N. Swaab D.F. Hoek R.M. Huitinga I. J. Neuropathol. Exp. Neurol. 2009; 68: 159-167Crossref PubMed Scopus (141) Google Scholar) but not on microglia (8Lyons A. Downer E.J. Crotty S. Nolan Y.M. Mills K.H. Lynch M.A. J. Neurosci. 2007; 27: 8309-8313Crossref PubMed Scopus (202) Google Scholar). A recent report has indicated that CD200 is expressed on reactive astrocytes in lesions from post-mortem multiple sclerosis brains (7Koning N. Swaab D.F. Hoek R.M. Huitinga I. J. Neuropathol. Exp. Neurol. 2009; 68: 159-167Crossref PubMed Scopus (141) Google Scholar). Expression of CD200R is mainly restricted to cells of the myeloid lineage and therefore, in the brain, has been identified on microglia (6Barclay A.N. Wright G.J. Brooke G. Brown M.H. Trends Immunol. 2002; 23: 285-290Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar, 7Koning N. Swaab D.F. Hoek R.M. Huitinga I. J. Neuropathol. Exp. Neurol. 2009; 68: 159-167Crossref PubMed Scopus (141) Google Scholar) but not on neurons (8Lyons A. Downer E.J. Crotty S. Nolan Y.M. Mills K.H. Lynch M.A. J. Neurosci. 2007; 27: 8309-8313Crossref PubMed Scopus (202) Google Scholar). The complementary expression of ligand and receptor on neurons and microglia, respectively, suggests that their interaction may play a role in modulating microglial activation, and recent evidence has supported this contention. The LPS-induced increases in expression of cell surface markers of microglial activation and inflammatory cytokine production were inhibited by the addition of neurons, and this attenuating effect of neurons was blocked by an anti-CD200 antibody (8Lyons A. Downer E.J. Crotty S. Nolan Y.M. Mills K.H. Lynch M.A. J. Neurosci. 2007; 27: 8309-8313Crossref PubMed Scopus (202) Google Scholar). This finding suggests that interaction of CD200 with its receptor has the capacity to modulate microglial activation.In CD200-deficient mice, increased microglial and/or macrophage activation has been described in several models of inflammation (e.g. facial nerve transection, experimental autoimmune encephalomyelitis, an animal model of arthritis (9Hoek R.M. Ruuls S.R. Murphy C.A. Wright G.J. Goddard R. Zurawski S.M. Blom B. Homola M.E. Streit W.J. Brown M.H. Barclay A.N. Sedgwick J.D. Science. 2000; 290: 1768-1771Crossref PubMed Scopus Google Scholar), and experimental autoimmune Hoek R.M. J. Sedgwick J.D. J. 2002; Full Text Full Text PDF PubMed Scopus Google of a CD200 the inflammatory changes in arthritis R.M. Yu K. J. Immunol. PubMed Scopus Google Scholar, R.M. Yu K. J. Immunol. 2002; PubMed Scopus Google Scholar), whereas the in experimental autoimmune in mice has been to increased expression of CD200 on neurons J. M. K. J. 2007; Full Text Full Text PDF PubMed Scopus Google expression of CD200 is with increased microglial activation in of and term of (8Lyons A. Downer E.J. Crotty S. Nolan Y.M. Mills K.H. Lynch M.A. J. Neurosci. 2007; 27: 8309-8313Crossref PubMed Scopus (202) Google Scholar, E.J. A. Mills K.H. E. Lynch M.A. PubMed Scopus Google Scholar), and synaptic long term potentiation is impaired microglial activation is increased R.M. D. F. Lynch M.A. 2007; PubMed Scopus Google Scholar, R.M. Mills K.H. Lynch M.A. J. Full Text Full Text PDF PubMed Scopus Google Scholar). we that glia prepared from CD200-deficient mice more to LPS and that this with evidence of impaired The that LPS and a effect on glia prepared from CD200−/− mice, due to the increase in expression of and TLR2 on these LTP was at CA1 of hippocampal slices prepared from compared with wild mice. LPS and LTP in slices prepared from CD200−/− mice. The evidence for an immunomodulatory role for CD200 and the loss of CD200 with a in synaptic and with increased expression of TLR2 and of CD200 has been associated with evidence of increased inflammatory changes in hippocampal tissue prepared from as as and (8Lyons A. Downer E.J. Crotty S. Nolan Y.M. Mills K.H. Lynch M.A. J. Neurosci. 2007; 27: 8309-8313Crossref PubMed Scopus (202) Google Scholar, A. K. Downer E.J. Murphy M. A. F. R. Mills K.H. Lynch M.A. 2009; 23: PubMed Scopus Google Scholar). this the effects of the and TLR2 LPS and were assessed on cytokine production in glia prepared from wild type and CD200−/− mice. The that of cells prepared from wild type mice in the of LPS increased release of the proinflammatory cytokines, IL-6, and and the effect was in the of and TNFα The effect of LPS was in cells prepared from CD200−/− mice of glia prepared from wild type mice in the of increased release of inflammatory The effect of was in glia prepared from CD200−/− mice, and this was in the of and TNFα wild type LPS and increased expression of these inflammatory cytokines, and the effect was in cells prepared from CD200−/− mice not These that activation by CD200 modulates cytokine release from of the effect of LPS on cytokine release prepared from microglia from wild type and CD200−/− mice for for wild type and CD200−/− cells, and TNFα This is consistent with the that microglia prepared from CD200−/− mice whereas with astrocytes that in an phenotype is as a of microglia, we that the of CD11b+ cells and CD11b+ cells was increased in a prepared from CD200−/− compared with wild type mice These that CD200 to of microglia a in a quiescent and that CD200 is expressed on its expression on astrocytes has been on reactive astrocytes in lesions from post-mortem brains of with multiple sclerosis (7Koning N. Swaab D.F. Hoek R.M. Huitinga I. J. Neuropathol. Exp. Neurol. 2009; 68: 159-167Crossref PubMed Scopus (141) Google Scholar). Here, was to CD200 expression on cells in a of astrocytes prepared from wild type and CD200−/− mice a and CD200 expression was on cells prepared from wild type mice, expression was on cells prepared from CD200−/− mice. expression of astrocytes were to membrane and for by CD200 was in but not whereas expression to the CD11b+ and CD11b+ cells increased in glia prepared from CD200−/− mice. is the of CD11b+ cells that stained positively for and as The is expressed on CD200 expression was on cells from from wild type but not CD200−/− mice. CD200 was in but not prepared from astrocytes from wild type mice. expression was in the possible explanation for the increase in of cells from CD200−/− mice to LPS and is the increase in expression of both TLR2 and in glia prepared from CD200−/− compared with wild type mice for a and that cell surface expression of both receptors was increased on CD11b+ cells from CD200−/− compared with wild type mice, but the increase was in the of TLR2 for and The increase in in cells prepared from CD200−/− compared with wild type mice for indicates that is in cells prepared from CD200−/− of TLR2 and is increased in glia prepared from CD200−/− mice. and TLR2 and the of CD11b+ cells that stained positively for and and TLR2 and were increased in glia prepared from CD200−/− compared with wild type mice for from and a that is increased in cells prepared from CD200−/− compared with wild type mice for deficiency is by inflammatory changes (9Hoek R.M. Ruuls S.R. Murphy C.A. Wright G.J. Goddard R. Zurawski S.M. Blom B. Homola M.E. Streit W.J. Brown M.H. Barclay A.N. Sedgwick J.D. Science. 2000; 290: 1768-1771Crossref PubMed Scopus Google Scholar, Hoek R.M. J. Sedgwick J.D. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), in the brain, microglial activation is with CD200 in brains of and in and (8Lyons A. Downer E.J. Crotty S. Nolan Y.M. Mills K.H. Lynch M.A. J. Neurosci. 2007; 27: 8309-8313Crossref PubMed Scopus (202) Google Scholar, A. K. Downer E.J. Murphy M. A. F. R. Mills K.H. Lynch M.A. 2009; 23: PubMed Scopus Google Scholar). this we expression of surface markers of microglial activation on cells prepared from CD200−/− and wild type mice and and that but not was increased in tissue prepared from CD200−/− compared with wild type mice for a and by indicated that was in CD11b+ cells but the of CD11b+ cells that were for MHCII and was increased for of microglial activation increased in cells prepared from CD200−/− mice. a and expression of but not was in glia prepared from CD200−/− compared with wild type mice for that the of CD11b+ cells was in wild type and CD200−/− but the of CD11b+ cells that stained positively for and and MHCII and was in glia from CD200−/− compared with wild type mice for has been as a of between macrophages express of and microglial express of D. PubMed Scopus Google that the numbers of CD11b+ cells were increased in of CD200−/− compared with wild type mice for and that CD200R expression TLR2 and on these cells was in tissue prepared from CD200−/− compared with wild type mice. The numbers of macrophages in the CD11b+ were in CD200−/− and wild type mice. of expression of in that both TLR2 and were increased in CD200−/− compared with wild type mice for and These changes that microglial activation in tissue of CD200−/− mice, and the changes in in the increase in expression of TLR2 in is the in Significantly, this was by a in LTP in CA1 the application of was in slices prepared from CD200−/− mice slices from compared with wild type mice slices from a of inflammatory from microglia this effect B. J. M. A. in Scholar, Murphy N. Murphy Lynch M.A. J. Neurosci. PubMed Google Scholar, 2004; PubMed Scopus Google Scholar, C.A. Lynch M.A. Neurosci. PubMed Scopus Google Scholar, A. K. Downer E.J. Murphy M. A. F. R. Mills K.H. Lynch M.A. 2009; 23: PubMed Scopus Google Scholar), we that whereas expression of and were in hippocampal tissue prepared from wild type and CD200−/− mice a and TNFα was increased for in hippocampal slices prepared from 2004; PubMed Scopus Google Scholar, C.A. Lynch M.A. Neurosci. PubMed Scopus Google Scholar, G. F. G. A. F. Neurosci. PubMed Scopus Google Scholar), application of TNFα to hippocampal slices impaired LTP to slices from increase in hippocampal expression of TLR2 and in CD200−/− mice is with a in numbers of cells were in the of CD200−/− compared with wild type mice for and expression of CD200R expression and was in tissue prepared from CD200−/− compared with wild type mice. TLR2 and expression on cells was in tissue prepared from CD200−/− compared with wild type mice, whereas TLR2 and expression were increased in hippocampal tissue prepared from CD200−/− compared with wild type mice for LTP in CA1 of hippocampal slices prepared from wild type mice slices from as in the of the was in slices prepared from CD200−/− mice to wild type mice slices from and for wild type and CD200−/− mice hippocampal expression of TNFα in CD200−/− mice may the associated in and were in tissue prepared from wild type and CD200−/− mice and but TNFα was increased for as by and of of TNFα to hippocampal slices impaired LTP to slices from to and cells prepared from CD200−/− mice increased to we that concentrations of LPS that exerted effect on LTP in wild type mice may in CD200−/− mice. of LPS to hippocampal slices from wild type mice for to inhibited LTP slices from compared with slices from a of LPS which exerted effect on LTP in slices prepared from wild type mice slices from LTP in slices from CD200−/− mice slices from to slices from is by LPS in CD200−/− mice. of LPS for to LTP in slices prepared from wild type mice slices from and the in the of the was compared with slices slices from and LTP in slices prepared from wild type mice was by of LPS for to slices from mice to slices from but LTP was in slices from CD200−/− mice slices from mice to slices from to and exerted a effect on inflammatory markers in cells prepared from CD200−/− mice, and we that its effect on LTP of to hippocampal slices prepared from wild type mice for to inhibited LTP slices from compared with slices from A of for to did not affect LTP in slices prepared from wild type mice slices from but LTP in slices prepared from CD200−/− mice slices from compared with slices from is by in CD200−/− mice. of for to LTP in slices prepared from wild type mice slices from and the in the of the was compared with slices slices from and LTP in slices prepared from wild type mice was by of for to slices from mice to slices from LTP was in slices from CD200−/− mice with slices from mice to slices from to and loss of CD200 has a impact on activation of microglia in to inflammatory probably because of increased expression of and TLR2 in and in LTP in was impaired in slices prepared from CD200-deficient mice activation of and by LPS and respectively, exerted a more profound effect on LTP in slices prepared from CD200−/− mice. that the increased expression of and TLR2 a explanation for the increased of CD200−/− mice to inflammatory and increased the release of proinflammatory cytokines, IL-6, and from described effects of and TLR2 A. K. Downer E.J. Murphy M. A. F. R. Mills K.H. Lynch M.A. 2009; 23: PubMed Scopus Google Scholar, S.M. J. Scopus Google Scholar, M. S. H. M. N. J. Gerber J. R. J. PubMed Scopus Google Scholar). exerted a effect on release of proinflammatory in glia prepared from CD200−/− mice, compared with wild type mice. Thus, activation of CD200 receptor by CD200 is to modulate inflammatory cytokine This with that the interaction of neurons and microglia by of CD200 receptor by CD200 microglial activation and production of (8Lyons A. Downer E.J. Crotty S. Nolan Y.M. Mills K.H. Lynch M.A. J. Neurosci. 2007; 27: 8309-8313Crossref PubMed Scopus (202) Google Scholar). the in which a was we that the modulating effect is a of the interaction between microglia and astrocytes, which we express is that CD200 is expressed on cell types, in the of astrocytes, expression to has been on reactive astrocytes in lesions from post-mortem brains of with multiple sclerosis (7Koning N. Swaab D.F. Hoek R.M. Huitinga I. J. Neuropathol. Exp. Neurol. 2009; 68: 159-167Crossref PubMed Scopus (141) Google Scholar). is that the of microglia in a microglial may a of the loss of the modulating effect of in glia in with LPS and and increased release of TNFα and to a in macrophages prepared from CD200−/− mice compared with wild type mice S. A. A. K. Bowdish Barclay A.N. S. Full Text Full Text PDF PubMed Scopus Google Scholar). macrophages prepared from CD200−/− mice, with LPS or expressed more MHCII and more inflammatory macrophages from wild type mice R.J. J. D. S. E. Sedgwick J.D. Barclay A.N. Immunol. 2008; PubMed Scopus Google Scholar). has been for that astrocytes of modulating have been to modulate LPS-induced changes in and production PubMed Scopus Google Scholar, K. A.N. F. PubMed Scopus Google Scholar) and expression of MHCII D. R. PubMed Scopus Google Scholar), effects that have been to release of The by which astrocytes modulate microglial have that to that inflammatory changes in CD200−/− mice. Thus, the and inflammation associated with experimental autoimmune encephalomyelitis, encephalitis, experimental autoimmune arthritis, and facial nerve more profound in CD200-deficient mice (9Hoek R.M. Ruuls S.R. Murphy C.A. Wright G.J. Goddard R. Zurawski S.M. Blom B. Homola M.E. Streit W.J. Brown M.H. Barclay A.N. Sedgwick J.D. Science. 2000; 290: 1768-1771Crossref PubMed Scopus Google Scholar, Hoek R.M. J. Sedgwick J.D. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, M. Sedgwick J.D. E. D. Neuropathol. PubMed Scopus (66) Google Scholar). the to an of was more in CD200-deficient compared with wild type mice R.J. J. D. S. E. Sedgwick J.D. Barclay A.N. Immunol. 2008; PubMed Scopus Google Scholar). has been that CD200R activation by a the associated with these and of macrophages on the of to the in the of CD200R and the and activation of R. Barclay A.N. Brown M.H. J. Immunol. 2009; PubMed Scopus Google Scholar), the by which these changes to the activation of to this we that increased expression of both and TLR2 was in glia prepared from CD200−/− mice, and this at in an explanation for the of CD200−/− mice to inflammatory TLR2 and to activation of in this the increased receptor expression in glia prepared from CD200−/− mice is with increased expression of which is of activation. These changes possible explanation for the increased of these cells to LPS and in the and in of CD200 increases expression of markers of microglial activation in CD200 deficiency was associated with enhanced expression of but not that these markers and MHCII were increased on cells prepared from CD200−/− mice. have the of the interaction between CD200 and CD200R in the quiescent of microglia and have that the and increases in microglial activation with CD200 expression on neurons (8Lyons A. Downer E.J. Crotty S. Nolan Y.M. Mills K.H. Lynch M.A. J. Neurosci. 2007; 27: 8309-8313Crossref PubMed Scopus (202) Google Scholar, E.J. A. Mills K.H. E. Lynch M.A. PubMed Scopus Google Scholar, A. K. Downer E.J. Murphy M. A. F. R. Mills K.H. Lynch M.A. 2009; 23: PubMed Scopus Google Scholar). The with the that microglia an inflammatory more (9Hoek R.M. Ruuls S.R. Murphy C.A. Wright G.J. Goddard R. Zurawski S.M. Blom B. Homola M.E. Streit W.J. Brown M.H. Barclay A.N. Sedgwick J.D. Science. 2000; 290: 1768-1771Crossref PubMed Scopus Google Scholar), and the of cells prepared from of CD200−/− mice was increased Hoek R.M. J. Sedgwick J.D. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar).In the has that neuroinflammatory with increased microglial activation, affect synaptic in and R.M. D. F. Lynch M.A. 2007; PubMed Scopus Google Scholar, B. Lynch M.A. Exp. Neurol. 2002; PubMed Scopus Google Scholar, S. A. C.A. PubMed Scopus Google Scholar, R. R. Nolan J. Lynch M.A. J. PubMed Scopus Google Scholar). These in this we the loss of CD200 with microglial activation and a in The evidence indicates that slices prepared from CD200−/− mice not LTP to the as slices prepared from wild type mice. One possible explanation for this is that which is increased in hippocampal tissue prepared from these mice, is from microglia and that TNFα LTP in which with evidence that a effect on LTP in in and in B. J. M. A. in Scholar, 2004; PubMed Scopus Google Scholar, G. F. G. A. F. Neurosci. PubMed Scopus Google Scholar).In addition to the in LTP in slices prepared from CD200−/− mice, the that a of LPS or which effects on LTP in wild type mice, LTP in slices prepared from CD200−/− mice. These for the that activation of TLR2 to of LTP and the effect of that a in CD200 to increased to inflammatory this is the effects of LPS or on LTP to changes in glia or a of a effect on and this is to that have expression of both in and in A. J.D. S. S. 2007; PubMed Scopus Google Scholar, J. Full Text Full Text PDF PubMed Scopus Google Scholar), have been to expression of TLR2 on neurons S. E. I. R. J. Immunol. PubMed Scopus Google Scholar). The of this finding for the is that the the in LTP may result from its to release IL-6, and TNFα from of these inflammatory has been to LTP B. J. M. A. in Scholar, M. S. M.C. G. F. F. J. 2000; PubMed Scopus Google Scholar, C.A. Lynch M.A. J. Neurosci. PubMed Google is an of evidence that CD200 deficiency is associated with increased inflammatory changes in several including the brain, the effect on is we report that activation of and neuroinflammatory changes in the of CD200 that CD200 deficiency a negative effect on A these changes is increased expression of these The the of CD200 as a in that by neuroinflammatory with loss of synaptic IntroductionCD200 is a type-1 membrane glycoprotein which has been identified as an immunosuppressive molecule, consistent with its expression on cells of the immune system, including dendritic cells, T and B cells, and endothelial and epithelial cells (1Barclay A.N. Immunology. 1981; 44: 727-736PubMed Google Scholar). Diverse immunomodulatory roles for CD200 have been reported; these include antigen-specific T cell responses, suppression of regulatory T cells (2Pallasch C.P. Ulbrich S. Brinker R. Hallek M. Uger R.A. Wendtner C.M. Leuk. Res. 2009; 33: 460-464Crossref PubMed Scopus (58) Google Scholar), cytotoxic T cell-mediated tumor suppression (3Siva A. Xin H. Qin F. Oltean D. Bowdish K.S. Kretz-Rommel A. Cancer Immunol. Immunother. 2008; 57: 987-996Crossref PubMed Scopus (74) Google Scholar), graft survival (4Gorczynski R.M. Yu K. Clark D. J. Immunol. 2000; 165: 4854-4860Crossref PubMed Scopus (65) Google Scholar), and apoptosis-associated immune tolerance (5Rosenblum M.D. Olasz E. Woodliff J.E. Johnson B.D. Konkol M.C. Gerber K.A. Orentas R.J. Sandford G. Truitt R.L. Blood. 2004; 103: 2691-2698Crossref PubMed Scopus (66) Google Scholar).In the brain, CD200 is expressed on neurons (6Barclay A.N. Wright G.J. Brooke G. Brown M.H. Trends Immunol. 2002; 23: 285-290Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar) and oligodendrocytes (7Koning N. Swaab D.F. Hoek R.M. Huitinga I. J. Neuropathol. Exp. Neurol. 2009; 68: 159-167Crossref PubMed Scopus (141) Google Scholar) but not on microglia (8Lyons A. Downer E.J. Crotty S. Nolan Y.M. Mills K.H. Lynch M.A. J. Neurosci. 2007; 27: 8309-8313Crossref PubMed Scopus (202) Google Scholar). A recent report has indicated that CD200 is expressed on reactive astrocytes in lesions from post-mortem multiple sclerosis brains (7Koning N. Swaab D.F. Hoek R.M. Huitinga I. J. Neuropathol. Exp. Neurol. 2009; 68: 159-167Crossref PubMed Scopus (141) Google Scholar). Expression of CD200R is mainly restricted to cells of the myeloid lineage and therefore, in the brain, has been identified on microglia (6Barclay A.N. Wright G.J. Brooke G. Brown M.H. Trends Immunol. 2002; 23: 285-290Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar, 7Koning N. Swaab D.F. Hoek R.M. Huitinga I. J. Neuropathol. Exp. Neurol. 2009; 68: 159-167Crossref PubMed Scopus (141) Google Scholar) but not on neurons (8Lyons A. Downer E.J. Crotty S. Nolan Y.M. Mills K.H. Lynch M.A. J. Neurosci. 2007; 27: 8309-8313Crossref PubMed Scopus (202) Google Scholar). The complementary expression of ligand and receptor on neurons and microglia, respectively, suggests that their interaction may play a role in modulating microglial activation, and recent evidence has supported this contention. The LPS-induced increases in expression of cell surface markers of microglial activation and inflammatory cytokine production were inhibited by the addition of neurons, and this attenuating effect of neurons was blocked by an anti-CD200 antibody (8Lyons A. Downer E.J. Crotty S. Nolan Y.M. Mills K.H. Lynch M.A. J. Neurosci. 2007; 27: 8309-8313Crossref PubMed Scopus (202) Google Scholar). This finding suggests that interaction of CD200 with its receptor has the capacity to modulate microglial activation.In CD200-deficient mice, increased microglial and/or macrophage activation has been described in several models of inflammation (e.g. facial nerve transection, experimental autoimmune encephalomyelitis, an animal model of arthritis (9Hoek R.M. Ruuls S.R. Murphy C.A. Wright G.J. Goddard R. Zurawski S.M. Blom B. Homola M.E. Streit W.J. Brown M.H. Barclay A.N. Sedgwick J.D. Science. 2000; 290: 1768-1771Crossref PubMed Scopus Google Scholar), and experimental autoimmune Hoek R.M. J. Sedgwick J.D. J. 2002; Full Text Full Text PDF PubMed Scopus Google of a CD200 the inflammatory changes in arthritis R.M. Yu K. J. Immunol. PubMed Scopus Google Scholar, R.M. Yu K. J. Immunol. 2002; PubMed Scopus Google Scholar), whereas the in experimental autoimmune in mice has been to increased expression of CD200 on neurons J. M. K. J. 2007; Full Text Full Text PDF PubMed Scopus Google expression of CD200 is with increased microglial activation in of and term of (8Lyons A. Downer E.J. Crotty S. Nolan Y.M. Mills K.H. Lynch M.A. J. Neurosci. 2007; 27: 8309-8313Crossref PubMed Scopus (202) Google Scholar, E.J. A. Mills K.H. E. Lynch M.A. PubMed Scopus Google Scholar), and synaptic long term potentiation is impaired microglial activation is increased R.M. D. F. Lynch M.A. 2007; PubMed Scopus Google Scholar, R.M. Mills K.H. Lynch M.A. J. Full Text Full Text PDF PubMed Scopus Google Scholar). we that glia prepared from CD200-deficient mice more to LPS and that this with evidence of impaired The that LPS and a effect on glia prepared from CD200−/− mice, due to the increase in expression of and TLR2 on these LTP was at CA1 of hippocampal slices prepared from compared with wild mice. LPS and LTP in slices prepared from CD200−/− mice. The evidence for an immunomodulatory role for CD200 and the loss of CD200 with a in synaptic and with increased expression of TLR2 and