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Differences in the early inflammatory responses to toxin-induced demyelination are associated with the age-related decline in CNS remyelination
Abstract
CNS remyelination occurs more rapidly in young adult rats than in old rats. Since the inflammatory response initiated by demyelination is an important trigger for remyelination, we address whether ageing changes in remyelination are associated with changes in the inflammatory response. Using a toxin model of demyelination, where the inflammatory response largely comprises macrophages, we show that there is a delay in both recruitment and activation of OX-42+ and macrophage scavenger receptor B+ macrophages following demyelination in older rats (10-13 months) compared to young rats (8-10 weeks). This difference is associated with a slower onset of increased expression of several chemokine mRNAs. However, many inflammatory cytokines have similar mRNA expression patterns, with the exception of IL-1beta, IL-6 and TNF-alpha, which have prolonged expression in the older animals. Differences in IL-1beta mRNA expression, a cytokine specifically implicated in CNS remyelination, are not reflected in differences in protein expression detected by immunocytochemistry. These data relate the age-associated delay in remyelination efficiency to changes in the macrophage and inflammatory mediator response to demyelination.
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“however, white matter demyelination injury provokes a reduced macrophage response in older rodents compared to younger controls (102).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [102]
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Rawji, K. S., Martinez, G. A. G., Sharma, A., & Franklin, R. J. M. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.05.006 · Cited by 84
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“…and Blakemore, 2005; Kotter et al., 2006), likely via the expression of growth factors and chemokines/cytokines shown to be required for effective remyelination in this and other models of CNS demyelination (Hinks and Franklin, 2000; Kotter et al., 2001, 2005; Li et al., 2005; Zhao et al., 2006).”
BackgroundMyelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells
Huang, J. K., Fancy, S. P. J., Zhao, C., Rowitch, D. H., ffrench‐Constant, C., & Franklin, R. J. M. (2011) · Neurotherapeutics · doi:10.1007/s13311-011-0065-x · Cited by 57
“First, rapid remyelination that occurs in young animals is associated with efficient removal of myelin debris in contrast to old animals that display slow remyelination and impaired clearance of myelin debris [40, 41].”
BackgroundSelf-citationRelapse severity and recovery in early pediatric multiple sclerosis
Fay, A. J., Mowry, E., Strober, J. B., & Waubant, E. (2012) · Multiple Sclerosis · doi:10.1177/1352458511431725 · Cited by 65
Microglia Diversity in Health and Multiple Sclerosis
Zia, S., Rawji, K. S., Michaels, N. J., Burr, M. K., Kerr, B. J., Healy, L. M., & Plemel, J. R. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.588021 · Cited by 70
Remyelination — An effective means of neuroprotection
Bruce, C. C., Zhao, C., & Franklin, R. J. M. (2009) · Hormones and Behavior · doi:10.1016/j.yhbeh.2009.06.004 · Cited by 65
Self-citationZveik, O., Rechtman, A., Ganz, T., & Vaknin‐Dembinsky, A. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00742-8 · Cited by 76
Regenerative Capacity of Macrophages for Remyelination
Rawji, K. S., Mishra, M. K., & Yong, V. W. (2016) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2016.00047 · Cited by 70
“In aging rodents receiving focal demyelination, there is a delay in the recruitment of macrophages/microglia associated with an alteration in several inflammatory cytokines and chemokines (Zhao et al., 2006).”
BackgroundInfluentialChio, J. C. T., Punjani, N., Hejrati, N., Zavvarian, M.-M., Hong, J., & Fehlings, M. G. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0120 · Cited by 67
Rawji, K. S., Kappen, J., Tang, W., Teo, W., Plemel, J. R., Stys, P. K., & Yong, V. W. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.2341-17.2018 · Cited by 75
“, 2016b) and is thought to underlie the deficiency in remyelination that occurs with senescence (Zhao et al., 2006; Ruckh et al., 2012).”
BackgroundInfluentialCNS Remyelination and the Innate Immune System
McMurran, C. E., Jones, C. A., Fitzgerald, D. C., & Franklin, R. J. M. (2016) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2016.00038 · Cited by 64
Self-citationTaking ageing into account in remyelination-based therapies for multiple sclerosis
Rist, J. M., & Franklin, R. J. M. (2008) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2008.04.027 · Cited by 55
“It has been shown that the inflammatory response is delayed in aged animals [35,36].”
Self-citationPhases and Phenotypes of Multiple Sclerosis
Kantarci, O. H. (2019) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/con.0000000000000737 · Cited by 62
Stoffels, J. M. J., Hoekstra, D., Franklin, R. J. M., Baron, W., & Zhao, C. (2014) · Glia · doi:10.1002/glia.22748 · Cited by 46
“For resin embedding and semi-thin sectioning, mice were perfused with 4% phosphate-buffered gluteraldehyde and subjected to a standard resin embedding process (Zhao et al., 2006).”
BackgroundMethodInfluentialSelf-citationAged rats have an altered immune response and worse outcomes after traumatic brain injury
Sun, M., Brady, R. D., Casillas-Espinosa, P. M., Wright, D. K., Semple, B. D., Kim, H. A., Mychasiuk, R., Sobey, C. G., O'Brien, T. J., Vinh, A., et al. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.04.038 · Cited by 59
Zhao, C., Fancy, S. P. J., ffrench-Constant, C., & Franklin, R. J. M. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.04.007 · Cited by 47
Self-citationProgressive Forms of Multiple Sclerosis
Zeydan, B., & Kantarci, O. H. (2017) · Neurologic Clinics · doi:10.1016/j.ncl.2017.08.006 · Cited by 52
Rodriguez, E. G., Wegner, C., Kreutzfeldt, M., Neid, K., Thal, D. R., Jürgens, T., Brück, W., Stadelmann, C., & Merkler, D. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1260-8 · Cited by 44
“Mechanisms contributing to such age-related effects may involve intrinsic determinants such as age-dependent epigenetic control of gene expression of OPCs [45] and extrinsic factors acting on OPCs in the lesion microenvironment [23, 52].”
BackgroundGlial aging and its impact on central nervous system myelin regeneration
Rawji, K. S., Neumann, B., & Franklin, R. J. M. (2022) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14933 · Cited by 47
Self-citationHampton, D. W., Innes, N., Merkler, D., Zhao, C., Franklin, R. J. M., & Chandran, S. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.01.018 · Cited by 43
Self-citationTargeting senescence to delay progression of multiple sclerosis
Oost, W., Talma, N., Meilof, J. F., & Laman, J. D. (2018) · Journal of Molecular Medicine · doi:10.1007/s00109-018-1686-x · Cited by 47
Myelin Pathogenesis and Functional Deficits Following SCI are Age-Associated
Siegenthaler, M. M., Ammon, D. L., & Keirstead, H. (2008) · Experimental Neurology · doi:10.1016/j.expneurol.2008.06.015 · Cited by 42
“This age-associated difference has been attributed to delayed growth factor gene expression, a decline in OPC colonization of OPC-depleted spinal cord tissue, and differences in early inflammatory responses (Chari et al., 2003; Hinks and Franklin, 2000; Zhao et al., 2006).”
A silver lining of neuroinflammation: Beneficial effects on myelination
Goldstein, E. Z., Church, J. S., Hesp, Z. C., Popovich, P. G., & McTigue, D. M. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.05.001 · Cited by 41
de Jong, J. M., Wang, P., Oomkens, M., & Baron, W. (2020) · Journal of Neuroscience Research · doi:10.1002/jnr.24582 · Cited by 41
McMurran, C. E., Guzman de la Fuente, A., Penalva, R., Ben Menachem-Zidon, O., Dombrowski, Y., Falconer, J., Gonzalez, G. A., Zhao, C., Krause, F. N., Young, A. M. H., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1905787116 · Cited by 39
“To create an environment that permits remyelination, endogenous microglia and infiltrating macrophages must clear myelin debris remaining from the disintegrated sheath (12), and also secrete proregenerative factors (10, 11, 13).”
Self-citationThe need to incorporate aged animals into the preclinical modeling of neurological conditions
Sun, M., McDonald, S. J., Brady, R. D., Collins‐Praino, L. E., Yamakawa, G. R., Monif, M., O'Brien, T. J., CLOUD, G. C., Sobey, C. G., Mychasiuk, R., et al. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.12.027 · Cited by 44
Deiva, K., Huppke, P., Banwell, B. L., Chitnis, T., Gärtner, J., Krupp, L., Waubant, E., Stites, T., Pearce, G., & Merschhemke, M. (2019) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2019-321124 · Cited by 39
Wang, P., Gorter, R. P., de Jonge, J. C., Nazmuddin, M., Zhao, C., Amor, S., Hoekstra, D., & Baron, W. (2018) · Glia · doi:10.1002/glia.23328 · Cited by 40
“Coincidentally, mRNA levels of TIMP1, a natural inhibitor of MMPs, were substantially increased at demyelination, and decreased at remyelination (14 DPL) compared with 5 DPL (Figure 1a).”
BackgroundMethodInfluentialSelf-citationThe remyelination Philosopher's Stone: stem and progenitor cell therapies for multiple sclerosis
Jadasz, J. J., Aigner, L., Rivera, F. J., & Küry, P. (2012) · Cell and Tissue Research · doi:10.1007/s00441-012-1331-x · Cited by 37
“Chemokines are of particular interest, since they have been shown to affect the differentiation and migration of NSPCs and of OPCs (Carbajal et al. 2010; Göttle et al. 2010; Patel et al. 2010).”
Backgroundde Jong, C. G. H. M., Gabius, H., & Baron, W. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03327-7 · Cited by 44
The influence of immunological stressors on traumatic brain injury
Sun, M., McDonald, S. J., Brady, R. D., O'Brien, T. J., & Shultz, S. R. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.01.007 · Cited by 41
“Similarly, pre-clinical studies have found that aged macrophages/monocytes also have impaired phagocytosis and chemotaxis (Zhao et al., 2006; Ruckh et al., 2012; Natrajan et al., 2015).”
Differentiation of mouse bone marrow derived stem cells toward microglia-like cells
Hinze, A., & Stolzing, A. (2011) · BMC Cell Biology · doi:10.1186/1471-2121-12-35 · Cited by 38
“In vitro, proliferating rat microglia have been reported to undergo telomere shortening [23] and aged microglia of several species have been observed to loose their ability to perform normal microglia functions [19,20,24-28].”
BackgroundToxin-Based Models to Investigate Demyelination and Remyelination
McMurran, C. E., Zhao, C., & Franklin, R. J. M. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9072-6_21 · Cited by 46
“In contrast to live cells, RNA and protein from a small region of CNS containing a lysolecithin lesion have been reliably used to investigate remyelination [82, 83].”
BackgroundSelf-citationMicroglia: Senescence Impairs Clearance of Myelin Debris
Thériault, P., & Rivest, S. (2016) · Current Biology · doi:10.1016/j.cub.2016.06.066 · Cited by 37
Myelin Repair: From Animal Models to Humans
Cayre, M., Falque, M., Mercier, O., Magalon, K., & Durbec, P. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.604865 · Cited by 44
Pioglitazone regulates myelin phagocytosis and multiple sclerosis monocytes
Natrajan, M. S., Komori, M., Kosa, P. F., Johnson, K. R., Wu, T., Franklin, R. J. M., & Bielekova, B. (2015) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.260 · Cited by 40
Self-citationRemyelination After Cuprizone-Induced Demyelination Is Accelerated in Juvenile Mice
Pfeifenbring, S., Nessler, S., Wegner, C., Stadelmann, C., & Brück, W. (2015) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000214 · Cited by 39
“Hence, rapid clearance of myelin debris by activated microglia enhances the process of remyelination (26, 28, 55, 56).”
Tracking the evolution of CNS remyelinating lesion in mice with neutral red dye
Baydyuk, M., Cha, D. S., Hu, J., Yamazaki, R., Miller, E. M., Smith, V. N., Kelly, K. A., & Huang, J. K. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1819343116 · Cited by 41
“Following demyelinating injury, the lesion site undergoes metabolic changes that influence cell reprogramming and differentiation, leading to oligodendrocyte maturation and myelin production (45, 46).”
BackgroundWelliver, R. R., Polanco, J. J., Seidman, R. A., Sinha, A. K., O’Bara, M. A., Khaku, Z. M., González, D. A. S., Nishiyama, A., Wess, J., Feltri, M. L., et al. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.1862-17.2018 · Cited by 45
“Focal demyelination of the young adult (8- to 11-week-old) mouse spinal cord was induced as previously described (Zhao et al., 2006).”
MethodZveik, O., Fainstein, N., Rechtman, A., Haham, N., Ganz, T., Lavon, I., Brill, L., & Vaknin‐Dembinsky, A. (2022) · Glia · doi:10.1002/glia.24165 · Cited by 35
“Immune cells are responsible for the clearance of myelin debris, which contains proteins that inhibit OPC differentiation (Baer et al., 2009; Kotter et al., 2006; Rosenberg et al., 2008; Ruckh et al., 2012; Syed et al., 2008; Zhao et al., 2006).”
BackgroundBlommaert, J., Schroyen, G., Vandenbulcke, M., Radwan, A., Smeets, A., Peeters, R. R., Sleurs, C., Neven, P., Wildiers, H. P. M. W., Amant, F. C., et al. (2019) · Human Brain Mapping · doi:10.1002/hbm.24753 · Cited by 40
Effect of body weight in the pathogenesis of ligature-induced periodontal disease in Wistar rats
Simch, R. P., Gaio, E. J., & Rösing, C. K. (2008) · Acta Odontologica Scandinavica · doi:10.1080/00016350802004672 · Cited by 32
“The literature considers rats as old at 10 months of age [33,34].”
BackgroundApproaches to Remyelination Therapies in Multiple Sclerosis
Wooliscroft, L., Silbermann, E., Cameron, M. H., & BOURDETTE, D. N. (2019) · Current Treatment Options in Neurology · doi:10.1007/s11940-019-0574-1 · Cited by 36
Paired Related Homeobox Protein 1 Regulates Quiescence in Human Oligodendrocyte Progenitors
Wang, J., Saraswat, D., Sinha, A. K., Polanco, J. J., Dietz, K., O’Bara, M. A., Pol, S. U., Shayya, H. J., & Sim, F. J. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.11.068 · Cited by 35
Wylot, B., Mieczkowski, J., Niedziolka, S., Kaminska, B., & Zawadzka, M. (2019) · Cells · doi:10.3390/cells9010099 · Cited by 29
“Moreover, the agedependent decrease in remyelination is attributed equally to the intrinsic properties of aging OPCs [23] and the impaired response of aging microglia and macrophages to demyelination [24,25].”
BackgroundImpaired regeneration in aged nerves: Clearing out the old to make way for the new
Scheib, J. L., & Höke, A. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.07.010 · Cited by 27
Nutritional factors and aging in demyelinating diseases
Adamo, A. M. (2013) · Genes & Nutrition · doi:10.1007/s12263-013-0360-8 · Cited by 32
“It is also important to consider the age-related modifications of the innate immune and growth factor responses to the demyelination process which interfere with myelin repair (Hinks and Franklin 2000; Zhao et al. 2006).”
BackgroundBeyond Clotting: A Role of Platelets in CNS Repair?
Rivera, F. J., Kazanis, I., Ghevaert, C., & Aigner, L. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00511 · Cited by 29
“…a potent inhibitor of OPC differentiation (Kotter et al., 2006; Baer et al., 2009)] through phagocytosis, and (ii) they secrete cytokines, growth- and neurotrophic factors that stimulate OPC responses to demyelination (Setzu et al., 2006; Zhao et al., 2006; Ruckh et al., 2012; Miron et al., 2013).”
BackgroundHosking, M., & Lane, T. E. (2009) · Current Immunology Reviews · doi:10.2174/157339509789504005 · Cited by 27
“Additionally, increased age negatively influences the capability OPCs to migrate, repopulate, and repair regions of damage in rodent models of demyelination [136-139].”
BackgroundMotavaf, M., Sadeghizadeh, M., & Javan, M. (2017) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-017-0472-6 · Cited by 25
Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation
Ossola, B., Zhao, C., Compston, A., Pluchino, S., Franklin, R. J. M., & Spillantini, M. G. (2015) · Glia · doi:10.1002/glia.22940 · Cited by 27
“Alkaline toluidine blue dye (0.5% Toluidine Blue1 0.5% Borax) (Sigma–Aldrich) was applied on semi-thin (1 lm) sections and heated with a Bunsen flame for 10 sec before washing with tap water (Zhao et al., 2006).”
InfluentialSelf-citationTan, G. A., Furber, K. L., Thangaraj, M. P., Sobchishin, L., Doucette, J. R., & Nazarali, A. J. (2017) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-017-0529-6 · Cited by 28
“There are also differences in microglia cell populations between the young and aging CNS (Grabert et al. 2016; Vela et al. 1995; Zhao et al. 2006), which are responsible for myelin debris clearance and promoting an environment conducive to neural repair.”
Metadata
- Authors
- Zhao, C., Li, W.-W., & Franklin, R. J. M.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Franklin, Robin J.M.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2006-09
- Volume
- 27
- Issue
- 9
- Pages
- 1298-1307
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2158151457
- Cited by
- 142
- References
- 45
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 7 · 2020: 8 · 2019: 16 · 2018: 10 · 2017: 11 · 2016: 10 · 2015: 10 · 2014: 8 · 2013: 8 · 2012: 4
- FWCI
- 3.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Multiple Sclerosis Society
- European Commission
- Topics
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- demyelination, aging, neuroinflammation, macrophages, OX-42, chemokines, inflammatory cytokines, IL-1β, interleukin-6, TNF-α, myelin oligodendrocyte glycoprotein, age-related decline
- MeSH terms
- Aging, Animals, Cell Count, Central Nervous System, Demyelinating Diseases, Disease Models, Animal, Female, Immunohistochemistry, Inflammation, Lysophosphatidylcholines, Macrophages, RNA, Messenger, Spinal Cord Diseases, Toxins, Biological, Gene Expression, Cytokines, Rats, Sprague-Dawley, In Situ Hybridization, Recovery of Function, Reverse Transcriptase Polymerase Chain Reaction, CD11b Antigen, Microarray Analysis, Rats
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