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Remote changes in gene expression after autoimmune demyelination: Grey matters
Journal of Neuroimmunology 205 (2008) 8–9
Contents lists available at ScienceDirect
Journal of Neuroimmunology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n e u r o i m
Editorial
Remote changes in gene expression after autoimmune demyelination: Grey matters Traditionally, multiple sclerosis (MS) has been viewed as a chronic inflammatory disease of the white matter with focal perivascular inflammation, demyelination and gliosis. Over the past 10 years, this description has been challenged in several aspects, with degenerative changes, including axonal injury, becoming a topic of interest. More recently, histopathological analyses, as well as innovative imaging approaches, have revealed the presence of extensive grey matter pathology in MS patients (Peterson et al., 2001). At the same time, imaging studies with advanced technological standards have highlighted the presence of subtle changes not only in lesions but also in normal-appearing CNS tissue, thus focusing on the so called “normalappearing white matter”—NAWM, (Filippi et al., 2005). Many of the pathological hallmarks of MS can be mimicked in rodent models of experimental autoimmune encephalomyelitis—EAE, (Gold et al., 2006), especially in myelin oligodendrocyte glycoprotein (MOG) induced EAE in the Dark Agouti (DA) rat which is characterized by a prevalence of spinal cord pathology (Storch et al., 1998). In this issue of JNI, Zeis et al. performed a gene expression analysis of normal-appearing white matter and normal-appearing grey matter in the brain after induction of MOG–EAE in the DA rat. While examination of white matter in the corpus callosum revealed only minor changes, the study disclosed significant alterations in the cerebral cortex including genes involved in mitochondrial function and a downregulation of glutamate receptors. The authors conclude that this reaction may reflect remote neuronal changes in the brain after an inflammatory attack on distant axons in the spinal cord. While importance of excitotoxic mechanisms in degenerative as well as demyelinating diseases has been recognized for some time (Pitt et al., 2000), the importance of mitochondrial proteins and also of the mitochondrial genome in EAE and MS has only recently been highlighted (Vogler et al., 2006; Yu et al., 2008). In contrast, distant changes in the CNS after neuronal or axonal lesions have already been described in different neurological disease paradigms, among them a toxic model of Huntington's disease (Topper et al., 1993), experimental autoimmune neuritis (Gehrmann et al., 1992), and spinal cord injury. In these models, remote changes were visualized by microglial activation distant from lesions which was very fast and led to local production of chemokines and cytokines (Zhao et al., 2007). This mechanism may be also of interest in autoimmune demyelination of the CNS where persistent microglial activation has been described, especially in chronic disease courses (Rasmussen et al., 2007). Yet, a systematic analysis of remote changes in gene expression distant from lesions has so far only been performed in a fimbria fornix axotomy model. Here, changes in axonal guidance molecules and the glial proteoglycan NG2 were described, thus again indicating modulation of the remote glial environment in addition to neuronal alterations (Kury et al., 2004a). Thus far, mechanisms governing neuronal changes distant from lesions in EAE and possibly also MS, are unclear. After a lesion of the 0165-5728/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2008.09.001
neurite, retrograde signalling from dendrites or axons to the neuronal soma is conceivable. Such signalling processes were convincingly shown in vitro for NF-κB as a master regulator of inflammatory processes (Wellmann et al., 2001), and also for ligand:neurotrophin receptor complexes like BDNF and its receptor, TrkB (Watson et al., 1999). Moreover, focal lesions may induce changes in electrical properties of neurons which finally lead to remote modulation of gene expression. This mechanism is of special interest in models of ischemia where cortical spreading depression may alter the pattern of gene expression (Kury et al., 2004b). Finally, focal inflammatory lesions in the spinal cord may lead to new functional circuits thus also resulting in remote changes in gene expression due to axonal plasticity (Kerschensteiner et al., 2004). While several investigators have elegantly characterized changes in the NAWM in MS and also in EAE, few have addressed functional changes in the normal-appearing grey matter (Herrero-Herranz et al., 2008). Alterations in cortical grey matter as described herein identify MOG–EAE as a more complex disease with not only focal, but rather diffuse changes in all parts of the CNS. Thus, it is conceivable that in the human disease, with its more widespread and diffuse inflammation, the cortex is involved to a much higher extent than hitherto believed. In particular, cortical pathology is probably the best correlate for cognitive impairment and possibly also fatigue, features which were for a long time neglected and which can result in significant disability in young MS patients. In the future, these changes deserve further attention in molecular studies, and may lead to innovative therapeutic strategies. References Filippi, M., Rocca, M.A., 2005. MRI evidence for multiple sclerosis as a diffuse disease of the central nervous system. J. Neurol. 252 (Suppl 5), v16–v24. Gehrmann, J., Gold, R., Linington, C., Lannes-Vieira, J., Wekerle, H., Kreutzberg, G.W., 1992. Spinal cord microglia in experimental allergic neuritis. Evidence for fast and remote activation. Lab. Invest. 67, 100–113. Gold, R., Linington, C., Lassmann, H., 2006. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129, 1953–1971. Herrero-Herranz, E., Pardo, L.A., Gold, R., Linker, R.A., 2008. Pattern of axonal injury in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis: implications for multiple sclerosis. Neurobiol. Dis. 30, 162–173. Kerschensteiner, M., Bareyre, F.M., Buddeberg, B.S., Merkler, D., Stadelmann, C., Bruck, W., Misgeld, T., Schwab, M.E., 2004. Remodeling of axonal connections contributes to recovery in an animal model of multiple sclerosis. J. Exp. Med. 200, 1027–1038. Kury, P., Abankwa, D., Kruse, F., Greiner-Petter, R., Muller, H.W., 2004a. Gene expression profiling reveals multiple novel intrinsic and extrinsic factors associated with axonal regeneration failure. Eur. J. Neurosci. 19, 32–42. Kury, P., Schroeter, M., Jander, S., 2004b. Transcriptional response to circumscribed cortical brain ischemia: spatiotemporal patterns in ischemic vs. remote nonischemic cortex. Eur. J. Neurosci. 19, 1708–1720. Peterson, J.W., Bo, L., Mork, S., Chang, A., Trapp, B.D., 2001. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann. Neurol. 50, 389–400. Pitt, D., Werner, P., Raine, C.S., 2000. Glutamate excitotoxicity in a model of multiple sclerosis. Nat. Med. 6, 67–70.
Editorial Rasmussen, S., Wang, Y., Kivisakk, P., Bronson, R.T., Meyer, M., Imitola, J., Khoury, S.J., 2007. Persistent activation of microglia is associated with neuronal dysfunction of callosal projecting pathways and multiple sclerosis-like lesions in relapsing– remitting experimental autoimmune encephalomyelitis. Brain 130, 2816–2829. Storch, M.K., Stefferl, A., Brehm, U., Weissert, R., Wallstrom, E., Kerschensteiner, M., Olsson, T., Linington, C., Lassmann, H., 1998. Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology. Brain Pathol. 8, 681–694. Topper, R., Gehrmann, J., Schwarz, M., Block, F., Noth, J., Kreutzberg, G.W., 1993. Remote microglial activation in the quinolinic acid model of Huntington's disease. Exp. Neurol. 123, 271–283. Vogler, S., Pahnke, J., Rousset, S., Ricquier, D., Moch, H., Miroux, B., Ibrahim, S.M., 2006. Uncoupling protein 2 has protective function during experimental autoimmune encephalomyelitis. Am. J. Pathol. 168, 1570–1575. Watson, F.L., Heerssen, H.M., Moheban, D.B., Lin, M.Z., Sauvageot, C.M., Bhattacharyya, A., Pomeroy, S.L., Segal, R.A., 1999. Rapid nuclear responses to target-derived neurotrophins require retrograde transport of ligand-receptor complex. J. Neurosci. 19, 7889–7900. Wellmann, H., Kaltschmidt, B., Kaltschmidt, C., 2001. Retrograde transport of transcription factor NF-kappa B in living neurons. J. Biol. Chem. 276, 11821–11829. Yu, X., Koczan, D., Sulonen, A.M., Akkad, D.A., Kroner, A., Comabella, M., Costa, G., Corongiu, D., Goertsches, R., Camina-Tato, M., Thiesen, H.J., Nyland, H.I., Mork, S.J., Montalban, X., Rieckmann, P., Marrosu, M.G., Myhr, K.M., Epplen, J.T., Saarela, J.,
9
Ibrahim, S.M., 2008. mtDNA nt13708A variant increases the risk of multiple sclerosis. PLoS ONE 3, e1530. Zhao, P., Waxman, S.G., Hains, B.C., 2007. Modulation of thalamic nociceptive processing after spinal cord injury through remote activation of thalamic microglia by cysteine chemokine ligand 21. J. Neurosci. 27, 8893–8902.
Ralf A. Linker⁎ Ralf Gold Department of Neurology, St. Josef Hospital, Ruhr-University Bochum Germany *Corresponding author. Department of Neurology, St. Josef Hospital, Ruhr-University Bochum, D-44791 Bochum, Germany. Tel.: +49 0 234 509 2411; fax: +49 0 234 509 2414. E-mail address: [email protected] (R. Linker). 8 September 2008
Contents lists available at ScienceDirect
Journal of Neuroimmunology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n e u r o i m
Editorial
Remote changes in gene expression after autoimmune demyelination: Grey matters Traditionally, multiple sclerosis (MS) has been viewed as a chronic inflammatory disease of the white matter with focal perivascular inflammation, demyelination and gliosis. Over the past 10 years, this description has been challenged in several aspects, with degenerative changes, including axonal injury, becoming a topic of interest. More recently, histopathological analyses, as well as innovative imaging approaches, have revealed the presence of extensive grey matter pathology in MS patients (Peterson et al., 2001). At the same time, imaging studies with advanced technological standards have highlighted the presence of subtle changes not only in lesions but also in normal-appearing CNS tissue, thus focusing on the so called “normalappearing white matter”—NAWM, (Filippi et al., 2005). Many of the pathological hallmarks of MS can be mimicked in rodent models of experimental autoimmune encephalomyelitis—EAE, (Gold et al., 2006), especially in myelin oligodendrocyte glycoprotein (MOG) induced EAE in the Dark Agouti (DA) rat which is characterized by a prevalence of spinal cord pathology (Storch et al., 1998). In this issue of JNI, Zeis et al. performed a gene expression analysis of normal-appearing white matter and normal-appearing grey matter in the brain after induction of MOG–EAE in the DA rat. While examination of white matter in the corpus callosum revealed only minor changes, the study disclosed significant alterations in the cerebral cortex including genes involved in mitochondrial function and a downregulation of glutamate receptors. The authors conclude that this reaction may reflect remote neuronal changes in the brain after an inflammatory attack on distant axons in the spinal cord. While importance of excitotoxic mechanisms in degenerative as well as demyelinating diseases has been recognized for some time (Pitt et al., 2000), the importance of mitochondrial proteins and also of the mitochondrial genome in EAE and MS has only recently been highlighted (Vogler et al., 2006; Yu et al., 2008). In contrast, distant changes in the CNS after neuronal or axonal lesions have already been described in different neurological disease paradigms, among them a toxic model of Huntington's disease (Topper et al., 1993), experimental autoimmune neuritis (Gehrmann et al., 1992), and spinal cord injury. In these models, remote changes were visualized by microglial activation distant from lesions which was very fast and led to local production of chemokines and cytokines (Zhao et al., 2007). This mechanism may be also of interest in autoimmune demyelination of the CNS where persistent microglial activation has been described, especially in chronic disease courses (Rasmussen et al., 2007). Yet, a systematic analysis of remote changes in gene expression distant from lesions has so far only been performed in a fimbria fornix axotomy model. Here, changes in axonal guidance molecules and the glial proteoglycan NG2 were described, thus again indicating modulation of the remote glial environment in addition to neuronal alterations (Kury et al., 2004a). Thus far, mechanisms governing neuronal changes distant from lesions in EAE and possibly also MS, are unclear. After a lesion of the 0165-5728/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2008.09.001
neurite, retrograde signalling from dendrites or axons to the neuronal soma is conceivable. Such signalling processes were convincingly shown in vitro for NF-κB as a master regulator of inflammatory processes (Wellmann et al., 2001), and also for ligand:neurotrophin receptor complexes like BDNF and its receptor, TrkB (Watson et al., 1999). Moreover, focal lesions may induce changes in electrical properties of neurons which finally lead to remote modulation of gene expression. This mechanism is of special interest in models of ischemia where cortical spreading depression may alter the pattern of gene expression (Kury et al., 2004b). Finally, focal inflammatory lesions in the spinal cord may lead to new functional circuits thus also resulting in remote changes in gene expression due to axonal plasticity (Kerschensteiner et al., 2004). While several investigators have elegantly characterized changes in the NAWM in MS and also in EAE, few have addressed functional changes in the normal-appearing grey matter (Herrero-Herranz et al., 2008). Alterations in cortical grey matter as described herein identify MOG–EAE as a more complex disease with not only focal, but rather diffuse changes in all parts of the CNS. Thus, it is conceivable that in the human disease, with its more widespread and diffuse inflammation, the cortex is involved to a much higher extent than hitherto believed. In particular, cortical pathology is probably the best correlate for cognitive impairment and possibly also fatigue, features which were for a long time neglected and which can result in significant disability in young MS patients. In the future, these changes deserve further attention in molecular studies, and may lead to innovative therapeutic strategies. References Filippi, M., Rocca, M.A., 2005. MRI evidence for multiple sclerosis as a diffuse disease of the central nervous system. J. Neurol. 252 (Suppl 5), v16–v24. Gehrmann, J., Gold, R., Linington, C., Lannes-Vieira, J., Wekerle, H., Kreutzberg, G.W., 1992. Spinal cord microglia in experimental allergic neuritis. Evidence for fast and remote activation. Lab. Invest. 67, 100–113. Gold, R., Linington, C., Lassmann, H., 2006. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129, 1953–1971. Herrero-Herranz, E., Pardo, L.A., Gold, R., Linker, R.A., 2008. Pattern of axonal injury in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis: implications for multiple sclerosis. Neurobiol. Dis. 30, 162–173. Kerschensteiner, M., Bareyre, F.M., Buddeberg, B.S., Merkler, D., Stadelmann, C., Bruck, W., Misgeld, T., Schwab, M.E., 2004. Remodeling of axonal connections contributes to recovery in an animal model of multiple sclerosis. J. Exp. Med. 200, 1027–1038. Kury, P., Abankwa, D., Kruse, F., Greiner-Petter, R., Muller, H.W., 2004a. Gene expression profiling reveals multiple novel intrinsic and extrinsic factors associated with axonal regeneration failure. Eur. J. Neurosci. 19, 32–42. Kury, P., Schroeter, M., Jander, S., 2004b. Transcriptional response to circumscribed cortical brain ischemia: spatiotemporal patterns in ischemic vs. remote nonischemic cortex. Eur. J. Neurosci. 19, 1708–1720. Peterson, J.W., Bo, L., Mork, S., Chang, A., Trapp, B.D., 2001. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann. Neurol. 50, 389–400. Pitt, D., Werner, P., Raine, C.S., 2000. Glutamate excitotoxicity in a model of multiple sclerosis. Nat. Med. 6, 67–70.
Editorial Rasmussen, S., Wang, Y., Kivisakk, P., Bronson, R.T., Meyer, M., Imitola, J., Khoury, S.J., 2007. Persistent activation of microglia is associated with neuronal dysfunction of callosal projecting pathways and multiple sclerosis-like lesions in relapsing– remitting experimental autoimmune encephalomyelitis. Brain 130, 2816–2829. Storch, M.K., Stefferl, A., Brehm, U., Weissert, R., Wallstrom, E., Kerschensteiner, M., Olsson, T., Linington, C., Lassmann, H., 1998. Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology. Brain Pathol. 8, 681–694. Topper, R., Gehrmann, J., Schwarz, M., Block, F., Noth, J., Kreutzberg, G.W., 1993. Remote microglial activation in the quinolinic acid model of Huntington's disease. Exp. Neurol. 123, 271–283. Vogler, S., Pahnke, J., Rousset, S., Ricquier, D., Moch, H., Miroux, B., Ibrahim, S.M., 2006. Uncoupling protein 2 has protective function during experimental autoimmune encephalomyelitis. Am. J. Pathol. 168, 1570–1575. Watson, F.L., Heerssen, H.M., Moheban, D.B., Lin, M.Z., Sauvageot, C.M., Bhattacharyya, A., Pomeroy, S.L., Segal, R.A., 1999. Rapid nuclear responses to target-derived neurotrophins require retrograde transport of ligand-receptor complex. J. Neurosci. 19, 7889–7900. Wellmann, H., Kaltschmidt, B., Kaltschmidt, C., 2001. Retrograde transport of transcription factor NF-kappa B in living neurons. J. Biol. Chem. 276, 11821–11829. Yu, X., Koczan, D., Sulonen, A.M., Akkad, D.A., Kroner, A., Comabella, M., Costa, G., Corongiu, D., Goertsches, R., Camina-Tato, M., Thiesen, H.J., Nyland, H.I., Mork, S.J., Montalban, X., Rieckmann, P., Marrosu, M.G., Myhr, K.M., Epplen, J.T., Saarela, J.,
9
Ibrahim, S.M., 2008. mtDNA nt13708A variant increases the risk of multiple sclerosis. PLoS ONE 3, e1530. Zhao, P., Waxman, S.G., Hains, B.C., 2007. Modulation of thalamic nociceptive processing after spinal cord injury through remote activation of thalamic microglia by cysteine chemokine ligand 21. J. Neurosci. 27, 8893–8902.
Ralf A. Linker⁎ Ralf Gold Department of Neurology, St. Josef Hospital, Ruhr-University Bochum Germany *Corresponding author. Department of Neurology, St. Josef Hospital, Ruhr-University Bochum, D-44791 Bochum, Germany. Tel.: +49 0 234 509 2411; fax: +49 0 234 509 2414. E-mail address: [email protected] (R. Linker). 8 September 2008