Absence of the Cellular Prion Protein Exacerbates and Prolongs Neuroinflammation in Experimental Autoimmune Encephalomyelitis

Although the physiological roles of the cellular prion protein (PrPC) remain to be fully elucidated, PrPC has been proposed to represent a potential regulator of cellular immunity. To test this hypothesis, we evaluated the consequences of PrPC deficiency on the course of experimental autoimmune encephalomyelitis induced by immunization with myelin oligodendrocyte glycoprotein peptide. Consistent with augmented proliferative responses and increased cytokine gene expression by myelin oligodendrocyte glycoprotein-primed Prnp−/− T cells, PrPC-deficient mice demonstrated more aggressive disease onset and a lack of clinical improvement during the chronic phase of experimental autoimmune encephalomyelitis. Acutely, Prnp−/− spinal cord, cerebellum, and forebrain exhibited higher levels of leukocytic infiltrates and pro-inflammatory cytokine gene expression, as well as increased spinal cord myelin basic protein and axonal loss. During the chronic phase, a remarkable persistence of leukocytic infiltrates was present in the forebrain and cerebellum, accompanied by an increase in interferon-γ and interleukin-17 transcripts. Attenuation of T cell-dependent neuroinflammation thus represents a potential novel function of PrPC. Although the physiological roles of the cellular prion protein (PrPC) remain to be fully elucidated, PrPC has been proposed to represent a potential regulator of cellular immunity. To test this hypothesis, we evaluated the consequences of PrPC deficiency on the course of experimental autoimmune encephalomyelitis induced by immunization with myelin oligodendrocyte glycoprotein peptide. Consistent with augmented proliferative responses and increased cytokine gene expression by myelin oligodendrocyte glycoprotein-primed Prnp−/− T cells, PrPC-deficient mice demonstrated more aggressive disease onset and a lack of clinical improvement during the chronic phase of experimental autoimmune encephalomyelitis. Acutely, Prnp−/− spinal cord, cerebellum, and forebrain exhibited higher levels of leukocytic infiltrates and pro-inflammatory cytokine gene expression, as well as increased spinal cord myelin basic protein and axonal loss. During the chronic phase, a remarkable persistence of leukocytic infiltrates was present in the forebrain and cerebellum, accompanied by an increase in interferon-γ and interleukin-17 transcripts. Attenuation of T cell-dependent neuroinflammation thus represents a potential novel function of PrPC. The cellular prion protein (PrPC), a highly conserved glycosylphosphatidylinositol-anchored cell surface glycoprotein concentrated in lipid rafts,1Taylor DR Hooper NM The prion protein and lipid rafts.Mol Membr Biol. 2006; 23: 89-99Crossref PubMed Scopus (217) Google Scholar is abundantly expressed in the central nervous system (CNS).2Kretzschmar HA Prusiner SB Stowring LE DeArmond SJ Scrapie prion proteins are synthesized in neurons.Am J Pathol. 1986; 122: 1-5PubMed Google Scholar, 3Brown DR Besinger A Herms JW Kretzschmar HA Microglial expression of the prion protein.Neuroreport. 1998; 9: 1425-1429Crossref PubMed Scopus (74) Google Scholar PrPC may serve as a receptor for a variety of putative ligands, including: heparan sulfate,4Pan T Wong BS Liu T Li R Petersen RB Sy MS Cell-surface prion protein interacts with glycosaminoglycans.Biochem J. 2002; 368: 81-90Crossref PubMed Scopus (124) Google Scholar laminin,5Graner E Mercadante AF Zanata SM Forlenza OV Cabral AL Veiga SS Juliano MA Roesler R Walz R Minetti A Izquierdo I Martins VR Brentani RR Cellular prion protein binds laminin and mediates neuritogenesis.Brain Res Mol Brain Res. 2000; 76: 85-92Crossref PubMed Scopus (258) Google Scholar neural cell adhesion molecule,6Schmitt-Ulms G Legname G Baldwin MA Ball HL Bradon N Bosque PJ Crossin KL Edelman GM DeArmond SJ Cohen FE Prusiner SB Binding of neural cell adhesion molecules (N-CAMs) to the cellular prion protein.J Mol Biol. 2001; 314: 1209-1225Crossref PubMed Scopus (301) Google Scholar various synaptic proteins,7Spielhaupter C Schatzl HM PrPC directly interacts with proteins involved in signaling pathways.J Biol Chem. 2001; 276: 44604-44612Crossref PubMed Scopus (188) Google Scholar and stress-inducible protein-1.8Zanata SM Lopes MH Mercadante AF Hajj GN Chiarini LB Nomizo R Freitas AR Cabral AL Lee KS Juliano MA de Oliveira E Jachieri SG Burlingame A Huang L Linden R Brentani RR Martins VR Stress-inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection.EMBO J. 2002; 21: 3307-3316Crossref PubMed Scopus (371) Google Scholar These ligand-receptor interactions suggest that PrPC could have a role in diverse processes, including neurodevelopment, synaptic function, neurite outgrowth, and neuronal survival. Evidence for the latter has supported the notion that neuroprotection is one physiological function of PrPC. For example, deletion of PrPC increased neuronal predisposition to damage by modulating susceptibility to apoptosis9Kurschner C Morgan JI Analysis of interaction sites in homo- and heteromeric complexes containing Bcl-2 family members and the cellular prion protein.Brain Res Mol Brain Res. 1996; 37: 249-258Crossref PubMed Google Scholar, 10Kuwahara C Takeuchi AM Nishimura T Haraguchi K Kubosaki A Matsumoto Y Saeki K Matsumoto Y Yokoyama T Itohara S Onodera T Prions prevent neuronal cell-line death.Nature. 1999; 400: 225-226Crossref PubMed Scopus (374) Google Scholar and the negative consequences of oxidative stress.11Brown DR Nicholas RS Canevari L Lack of prion protein expression results in a neuronal phenotype sensitive to stress.J Neurosci Res. 2002; 67: 211-224Crossref PubMed Scopus (199) Google Scholar, 12Wong BS Liu T Li R Pan T Petersen RB Smith MA Gambetti P Perry G Manson JC Brown DR Sy MS Increased levels of oxidative stress markers detected in the brains of mice devoid of prion protein.J Neurochem. 2001; 76: 565-572Crossref PubMed Scopus (152) Google Scholar, 13Rachidi W Vilette D Guiraud P Arlotto M Riondel J Laude H Lehmann S Favier A Expression of prion protein increases cellular copper binding and antioxidant enzyme activities but not copper delivery.J Biol Chem. 2003; 278: 9064-9072Crossref PubMed Scopus (181) Google Scholar Furthermore, in vivo studies demonstrated that PrPC-deficient mice were more prone to seizure induction,14Walz R Amaral OB Rockenbach IC Roesler R Izquierdo I Cavalheiro EA Martins VR Brentani RR Increased sensitivity to seizures in mice lacking cellular prion protein.Epilepsia. 1999; 40: 1679-1682Crossref PubMed Scopus (168) Google Scholar and exhibited an increased extent of cerebral damage following an ischemic challenge.15Weise J Sandau R Schwarting S Crome O Wrede A Schulz-Schaeffer W Zerr I Bahr M Deletion of cellular prion protein results in reduced Akt activation, enhanced postischemic caspase-3 activation, and exacerbation of ischemic brain injury.Stroke. 2006; 37: 1296-1300Crossref PubMed Scopus (139) Google Scholar In contrast, adenovirus-mediated PrPC overexpression reduced CNS damage in a rat model of cerebral ischemia.16Shyu WC Lin SZ Chiang MF Ding DC Li KW Chen SF Yang HI Li H Overexpression of PrPC by adenovirus-mediated gene targeting reduces ischemic injury in a stroke rat model.J Neurosci. 2005; 25: 8967-8977Crossref PubMed Scopus (105) Google Scholar While the mechanism(s) underlying these phenomena remain unclear, such in vivo findings have lent strong support to the idea that PrPC may have a neuroprotective function. PrPC is expressed on the surface of cells of the human and murine lympho-hematopoietic system, including dendritic cells (DCs), follicular dendritic cells, macrophages/microglia, and in humans, T-lymphocytes.17Isaacs JD Jackson GS Altmann DM The role of the cellular prion protein in the immune system.Clin Exp Immunol. 2006; 146: 1-8Crossref PubMed Scopus (68) Google Scholar, 18Dodelet VC Cashman NR Prion protein expression in human leukocyte differentiation.Blood. 1998; 91: 1556-1561Crossref PubMed Google Scholar, 19Burthem J Urban B Pain A Roberts DJ The normal cellular prion protein is strongly expressed by myeloid dendritic 2001; PubMed Scopus Google Scholar, R Liu D G Liu T JD Huang Petersen RB Gambetti P Sy MS The expression and potential function of cellular prion protein in human Immunol. 2001; PubMed Scopus Google Scholar to the in mice PrPC was detected in a of B and T T Li R Wong BS Liu D Pan T Petersen RB Gambetti P Sy MS cellular prion protein is expressed on of murine Immunol. 2001; PubMed Scopus Google Scholar, SM expression of prion protein in of the 2002; PubMed Scopus Google Scholar studies have that PrPC may a role in T cell Brown KL Manson J and the cellular of the prion PubMed Scopus Google Scholar the of Chiarini LB Martins MA Linden R The cellular prion protein and Biol. 2005; PubMed Scopus Google Scholar and T C P N E S P P C C of cellular prion protein in interactions T cells and dendritic Immunol. 2006; Google Scholar The interaction T cells and represents a for the of immune and the that T cells and the that PrPC a role in immune system PrPC the in vivo activities of cells of the immune system during normal autoimmune T PrPC is expressed in cells of the murine immune system, we that mice lacking this an in to an induced T autoimmune that mice lacking PrPC more and that to during the chronic phase of novel phenotype was accompanied by of of and more spinal cord as well as a persistence of and T cell infiltrates in the PrPC thus to be an regulator of T with a of the prion gene of the I H M Y H DeArmond SJ Prusiner SB M C and of mice lacking the neuronal PubMed Scopus Google Scholar and a and B were the and to Prnp−/− and in the The I for to a were in of the To to were the of the with of myelin oligodendrocyte glycoprotein leukocyte and as a potential for 2002; PubMed Scopus Google Scholar in with of was J Wong G D A J L is a cytokine in 1998; PubMed Scopus Google Scholar were for clinical for and Prnp−/− a to J Wong G D A J L is a cytokine in 1998; PubMed Scopus Google Scholar as 1 of one of and and were by were in with on and of were and Prnp−/− and T cells were by negative dendritic cell and T cell in with the T cells were in containing and cells were with 1 for For 1 of T cells were in in and with to prevent were with of PrPC and with of cells were and a with and cells and Prnp−/− mice were a of 1 and with for cells with as the were the as for and Prnp−/− were in and T cells were the T cell and a of and T cells were in containing and were for 1 to were and on a and spinal were in and in as leukocyte and as a potential for 2002; PubMed Scopus Google Scholar and spinal were by was by axonal in in spinal cord and a and system to of axonal damage was the and the J as S J S K C receptor and neuroinflammation and in a model of Neurosci. 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PubMed Scopus Google expression, and is to as well as oligodendrocyte and neuronal cell damage in L G and Neurosci 2005; PubMed Scopus Google Scholar that PrPC deficiency has been to increase cellular susceptibility to oxidative DR Nicholas RS Canevari L Lack of prion protein expression results in a neuronal phenotype sensitive to stress.J Neurosci Res. 2002; 67: 211-224Crossref PubMed Scopus (199) Google Scholar, 12Wong BS Liu T Li R Pan T Petersen RB Smith MA Gambetti P Perry G Manson JC Brown DR Sy MS Increased levels of oxidative stress markers detected in the brains of mice devoid of prion protein.J Neurochem. 2001; 76: 565-572Crossref PubMed Scopus (152) Google Scholar, 13Rachidi W Vilette D Guiraud P Arlotto M Riondel J Laude H Lehmann S Favier A Expression of prion protein increases cellular copper binding and antioxidant enzyme activities but not copper delivery.J Biol Chem. 2003; 278: 9064-9072Crossref PubMed Scopus (181) Google Scholar of the CNS damage that we in Prnp−/− was to by the and present in the of Prnp−/− The levels of in the T cells and the CNS Prnp−/− were in with the of cells during the phase of this cytokine to have an role in cell activation, as well as in the of and A Oliveira of 1999; PubMed Scopus Google Scholar, L A of the in the of T PubMed Scopus Google Scholar Increased levels of were in the chronic phase of the disease in the Prnp−/− as were transcripts. the were by the cell S I is the of in experimental autoimmune PubMed Scopus Google Scholar by of and cells was not the may to the of in to role in on the L A of the in the of T PubMed Scopus Google Scholar to in the chronic of Prnp−/− is that of as a gene that was in chronic in C G R A E H A S B J P A N N SJ R L of in autoimmune 2002; PubMed Scopus Google Scholar of the prion gene to the leukocytic in the mice of PrPC were to of T cell to T cell the the of T cell an chronic neuroinflammation be the spinal is of with have been of disease with mice in the of in with of cerebellum, DM A of experimental autoimmune encephalomyelitis with brain and and and 2000; PubMed Scopus Google Scholar with the increased and CNS damage of the Prnp−/− and in with an of was a in the extent of the forebrain and in Prnp−/− mice as with prion gene deficiency was with a more aggressive disease and with a in the of to a disease that was more concentrated on CNS in mice thus represents a novel model of with the in the chronic phase in an for novel that may findings the that human prion gene the clinical course of be of to the lack of PrPC of immune such are to for of the and and for the and for the with

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