CoChat
Sign Up
Cited by 158Nerve injury and regenerationPeripheral Neuropathies and DisordersPain Mechanisms and Treatments

Inflammaging impairs peripheral nerve maintenance and regeneration

Open access
Büttner, Robert, Schulz, Alexander, Reuter, Michael, Akula, Asha K., Mindos, Thomas, Carlstedt, Annemarie, Riecken, Lars B., Baader, Stephan L. +2 more·2018·Aging Cell
DOI 10.1111/acel.12833PMC PMC6260910
Open this paper in CoChat — free accountOpen PDF

Abstract

The regenerative capacity of peripheral nerves declines during aging, contributing to the development of neuropathies, limiting organism function. Changes in Schwann cells prompt failures in instructing maintenance and regeneration of aging nerves; molecular mechanisms of which have yet to be delineated. Here, we identified an altered inflammatory environment leading to a defective Schwann cell response, as an underlying mechanism of impaired nerve regeneration during aging. Chronic inflammation was detected in intact uninjured old nerves, characterized by increased macrophage infiltration and raised levels of monocyte chemoattractant protein 1 (MCP1) and CC chemokine ligand 11 (CCL11). Schwann cells in the old nerves appeared partially dedifferentiated, accompanied by an activated repair program independent of injury. Upon sciatic nerve injury, an initial delayed immune response was followed by a persistent hyperinflammatory state accompanied by a diminished repair process. As a contributing factor to nerve aging, we showed that CCL11 interfered with Schwann cell differentiation in vitro and in vivo . Our results indicate that increased infiltration of macrophages and inflammatory signals diminish regenerative capacity of aging nerves by altering Schwann cell behavior. The study identifies CCL11 as a promising target for anti‐inflammatory therapies aiming to improve nerve regeneration in old age.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1111/acel.12833

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • CCL11 efficiently crosses the blood brain barrier, has been implicated in neuroinflammatory disorders and SARS-CoV-2 cognitive impairment, and impairs neurogenesis.

    “CCL11 efficiently crosses the blood brain barrier56, has been implicated in neuroinflammatory disorders and SARS-CoV-2 (COVID-19) cognitive impairment57,58, and impairs neurogenesis54,58,59.”

    From Senescent-like microglia limit remyelination through the senescence associated secretory phenotype (2025) · cites this paper as [59]

    This source is cited for the neurogenesis clause. The Results section reports that CCL11 reduces Schwann-cell myelination and remyelination, but those processes are not neurogenesis. Searches for neurogenesis and the generation of new neurons found no passage in our copy establishing that CCL11 impairs neurogenesis; the blood–brain barrier and COVID-19 clauses carry other citations. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 40

  1. Arthur‐Farraj, P. J., Latouche, M., Wilton, D. K., Quintes, S., Chabrol, E., Banerjee, A., … Jessen, K. R. (2012). c‐ Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration. Neuron, 75, 633– 647. 10.1016/j.neuron.2012.06.021 22920255 PMC3657176 · DOI
  2. Boivin, A., Pineau, I., Barrette, B., Filali, M., Vallieres, N., Rivest, S., & Lacroix, S. (2007). Toll‐like receptor signaling is critical for Wallerian degeneration and functional recovery after peripheral nerve injury. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience, 27, 12565– 12576. 10.1523/JNEUROSCI.3027-07.2007 18003835 PMC6673340 · DOI
  3. Bradman, M. J., Ferrini, F., Salio, C., & Merighi, A. (2015). Practical mechanical threshold estimation in rodents using von Frey hairs/Semmes‐ Weinstein monofilaments: Towards a rational method. Journal of Neuroscience Methods, 255, 92– 103. 10.1016/j.jneumeth.2015.08.010 26296284 · DOI
  4. Cattin, A. L., Burden, J. J., Van Emmenis, L., Mackenzie, F. E., Hoving, J. J., Garcia Calavia, N., … Lloyd, A. C. (2015). Macrophage‐induced blood vessels guide schwann cell‐mediated regeneration of peripheral nerves. Cell, 162, 1127– 1139. 10.1016/j.cell.2015.07.021 26279190 PMC4553238 · DOI
  5. Chen, Z. L., Yu, W. M., & Strickland, S. (2007). Peripheral regeneration. Annual Review of Neuroscience, 30, 209– 233. 10.1146/annurev.neuro.30.051606.094337 17341159 · DOI
  6. Deshmane, S. L., Kremlev, S., Amini, S., & Sawaya, B. E. (2009). Monocyte chemoattractant protein‐1 (MCP‐ 1): An overview. Journal of Interferon & Cytokine Research, 29(6), 313– 326. 10.1089/jir.2008.0027 19441883 PMC2755091 · DOI · Paper page
  7. Dubovy, P., Jancalek, R., & Kubek, T. (2013). Role of inflammation and cytokines in peripheral nerve regeneration. International Review of Neurobiology, 108, 173– 206. 24083435
  8. Duraku, L. S., Hossaini, M., Hoendervangers, S., Falke, L. L., Kambiz, S., Mudera, V. C., … Ruigrok, T. J. (2012). Spatiotemporal dynamics of re‐innervation and hyperinnervation patterns by uninjured CGRP fibers in the rat foot sole epidermis after nerve injury. Molecular Pain, 8, 61 10.1186/1744-8069-8-61 22935198 PMC3492210 · DOI
  9. Fenrich, K., & Gordon, T. (2004). Canadian Association of Neuroscience review: Axonal regeneration in the peripheral and central nervous systems– current issues and advances. Canadian Journal of Neurological Sciences, 31, 142– 156. 10.1017/S0317167100053798 15198438 · DOI
  10. Fey, A., Schachner, M., & Irintchev, A. (2010). A novel motion analysis approach reveals late recovery in C57BL/6 mice and deficits in NCAM‐deficient mice after sciatic nerve crush. Journal of Neurotrauma, 27, 815– 828. 10.1089/neu.2009.1217 20121417 · DOI
  11. Flurkey, K., Currer, J. M., & Harrison, D. E. (2007). The mouse in aging research In Fox J. G., et al. (Eds.), The mouse in biomedical research (pp. 637– 672). Burlington, MA: American College Laboratory Animal Medicine (Elsevier).
  12. Gao, J. L., Sen, A. I., Kitaura, M., Yoshie, O., Rothenberg, M. E., Murphy, P. M., & Luster, A. D. (1996). Identification of a mouse eosinophil receptor for the CC chemokine eotaxin. Biochemical and Biophysical Research Communications, 223, 679– 684. 10.1006/bbrc.1996.0955 8687456 · DOI
  13. Harauz, G., & Boggs, J. M. (2013). Myelin management by the 18.5‐kDa and 21.5‐ kDa classic myelin basic protein isoforms. Journal of Neurochemistry, 125, 334– 361. 23398367 PMC3700880
  14. Harrisingh, M. C., Perez‐Nadales, E., Parkinson, D. B., Malcolm, D. S., Mudge, A. W., & Lloyd, A. C. (2004). The Ras/Raf/ERK signalling pathway drives Schwann cell dedifferentiation. EMBO Journal, 23, 3061– 3071. 10.1038/sj.emboj.7600309 15241478 PMC514926 · DOI
  15. He, L., Yadgarov, A., Sharif, S., & McCluskey, L. P. (2012). Aging profoundly delays functional recovery from gustatory nerve injury. Neuroscience, 209, 208– 218. 10.1016/j.neuroscience.2012.02.012 22387273 PMC3678285 · DOI
  16. Herranz, S., Traves, P. G., Luque, A., & Hortelano, S. (2012). Role of the tumor suppressor ARF in macrophage polarization: Enhancement of the M2 phenotype in ARF‐deficient mice. Oncoimmunology, 1, 1227– 1238. 10.4161/onci.21207 23243586 PMC3518495 · DOI
  17. Huebner, E. A., & Strittmatter, S. M. (2009). Axon regeneration in the peripheral and central nervous systems. Results and Problems in Cell Differentiation, 48, 339– 351. 19582408 PMC2846285
  18. Jessen, K. R., & Mirsky, R. (2008). Negative regulation of myelination: Relevance for development, injury, and demyelinating disease. Glia, 56, 1552– 1565. 18803323
  19. Jessen, K. R., Mirsky, R., & Lloyd, A. C. (2015). Schwann cells: development and role in nerve repair. Cold Spring Harbor Perspectives in Biology, 7, a020487 10.1101/cshperspect.a020487 25957303 PMC4484967 · DOI
  20. Jose, P. J., Griffiths‐Johnson, D. A., Collins, P. D., Walsh, D. T., Moqbel, R., Totty, N. F., … Williams, T. J. (1994). Eotaxin: A potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation. The Journal of Experimental Medicine, 179, 881– 887. 10.1084/jem.179.3.881 7509365 PMC2191401 · DOI
  21. Kang, H., & Lichtman, J. W. (2013). Motor axon regeneration and muscle reinnervation in young adult and aged animals. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience, 33, 19480– 19491. 10.1523/JNEUROSCI.4067-13.2013 24336714 PMC6618761 · DOI
  22. Kato, N., Nemoto, K., Kawaguchi, M., Amako, M., Arino, H., & Fujikawa, K. (2001). Influence of chronic inflammation in peripheral target tissue on recovery of crushed nerve injury. Journal of Orthopaedic Science, 6, 419– 423. 10.1007/s007760170008 11845351 · DOI
  23. Kiguchi, N., Maeda, T., Kobayashi, Y., Fukazawa, Y., & Kishioka, S. (2010). Macrophage inflammatory protein‐1alpha mediates the development of neuropathic pain following peripheral nerve injury through interleukin‐ 1beta up‐regulation. Pain, 149, 305– 315. 20223588
  24. Kovacic, U., Sketelj, J., & Bajrovic, F. F. (2009). Chapter 26: Age‐related differences in the reinnervation after peripheral nerve injury. International Review of Neurobiology, 87, 465– 482. 19682655
  25. Ma, C. H., Omura, T., Cobos, E. J., Latremoliere, A., Ghasemlou, N., Brenner, G. J., … Woolf, C. J. (2011). Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice. The Journal of Clinical Investigation, 121, 4332– 4347. 21965333 PMC3223863
  26. Mietto, B. S., Mostacada, K., & Martinez, A. M. (2015). Neurotrauma and inflammation: CNS and PNS responses. Mediators of Inflammation, 2015, 251204 10.1155/2015/251204 25918475 PMC4397002 · DOI
  27. Morris, T., Stables, M., Hobbs, A., de Souza, P., Colville‐Nash, P., Warner, T., … Gilroy, D. W. (2009). Effects of low‐dose aspirin on acute inflammatory responses in humans. Journal of Immunology, 183, 2089– 2096. 10.4049/jimmunol.0900477 19597002 · DOI
  28. Napoli, I., Noon, L. A., Ribeiro, S., Kerai, A. P., Parrinello, S., Rosenberg, L. H., … Lloyd, A. C. (2012). A central role for the ERK‐signaling pathway in controlling Schwann cell plasticity and peripheral nerve regeneration in vivo. Neuron, 73, 729– 742. 22365547
  29. Painter, M. W., Brosius Lutz, A., Cheng, Y. C., Latremoliere, A., Duong, K., Miller, C. M., … Woolf, C. J. (2014). Diminished Schwann cell repair responses underlie age‐associated impaired axonal regeneration. Neuron, 83, 331– 343. 10.1016/j.neuron.2014.06.016 25033179 PMC4106408 · DOI
  30. Parkinson, D. B., Bhaskaran, A., Arthur‐Farraj, P., Noon, L. A., Woodhoo, A., Lloyd, A. C., … Jessen, K. R. (2008). c‐ Jun is a negative regulator of myelination. The Journal of Cell Biology, 181, 625– 637. 10.1083/jcb.200803013 18490512 PMC2386103 · DOI
  31. Rowlatt, C., Chesterman, F. C., & Sheriff, M. U. (1976). Lifespan, age changes and tumour incidence in an ageing C57BL mouse colony. Laboratory Animals, 10, 419– 442. 10.1258/002367776780956917 979138 · DOI
  32. Scheib, J. L., & Hoke, A. (2016). An attenuated immune response by Schwann cells and macrophages inhibits nerve regeneration in aged rats. Neurobiology of Aging, 45, 1– 9. 27459920
  33. Schulz, A., Buttner, R., Hagel, C., Baader, S. L., Kluwe, L., Salamon, J., … Morrison, H. (2016). The importance of nerve microenvironment for schwannoma development. Acta Neuropathologica, 132(2), 289– 307. 10.1007/s00401-016-1583-8 27236462 PMC4947119 · DOI
  34. Schulz, A., Walther, C., Morrison, H., & Bauer, R. (2014). In vivo electrophysiological measurements on mouse sciatic nerves. Journal of Visualized Experiments, 13(86). 10.3791/51181. PMC4166965 24747166 · DOI
  35. Shaw, A. C., Joshi, S., Greenwood, H., Panda, A., & Lord, J. M. (2010). Aging of the innate immune system. Current Opinion in Immunology, 22, 507– 513. 10.1016/j.coi.2010.05.003 20667703 PMC4034446 · DOI · Paper page
  36. Tofaris, G. K., Patterson, P. H., Jessen, K. R., & Mirsky, R. (2002). Denervated Schwann cells attract macrophages by secretion of leukemia inhibitory factor (LIF) and monocyte chemoattractant protein‐1 in a process regulated by interleukin‐6 and LIF. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience, 22, 6696– 6703. 10.1523/JNEUROSCI.22-15-06696.2002 12151548 PMC6758146 · DOI
  37. van Rossum, D., Hilbert, S., Strassenburg, S., Hanisch, U. K., & Bruck, W. (2008). Myelin‐phagocytosing macrophages in isolated sciatic and optic nerves reveal a unique reactive phenotype. Glia, 56, 271– 283. 10.1002/glia.20611 18069669 · DOI
  38. Verdu, E., Ceballos, D., Vilches, J. J., & Navarro, X. (2000). Influence of aging on peripheral nerve function and regeneration. Journal of the Peripheral Nervous System, 5, 191– 208. 10.1046/j.1529-8027.2000.00026.x 11151980 · DOI
  39. Villeda, S. A., Luo, J., Mosher, K. I., Zou, B., Britschgi, M., Bieri, G., … Wyss‐Coray, T. (2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature, 477, 90– 94. 10.1038/nature10357 21886162 PMC3170097 · DOI · Paper page
  40. Wang, Y. J., Zhou, C. J., Shi, Q., Smith, N., & Li, T. F. (2007). Aging delays the regeneration process following sciatic nerve injury in rats. Journal of Neurotrauma, 24, 885– 894. 10.1089/neu.2006.0156 17518542 · DOI

Cited by

Sorted by citations

Authors
Büttner, R., Schulz, A., Reuter, M., Akula, A. K., Mindos, T., Carlstedt, A., Riecken, L. B., Baader, S. L., Bauer, R., & Morrison, H.
Affiliations
  • Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
  • Yale University (US)
  • University of Bonn (DE)
  • Jena University Hospital (DE)
Corresponding author
Morrison, Helen
ORCID
Venue
Aging Cell
Publisher
Wiley
Published
2018-08-31
Volume
17
Issue
6
Pages
e12833-e12833
ISSN
  • 1474-9718 (ISSN-L)
  • 1474-9726
DOI
10.1111/acel.12833
PMC
PMC6260910
OpenAlex
W2888804528
Cited by
158
References
4
Citations by year
2026: 17 · 2025: 23 · 2024: 35 · 2023: 21 · 2022: 17 · 2021: 22 · 2020: 17 · 2019: 6
FWCI
5.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Aging Cell (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
Funders
  • Leibniz-Gemeinschaft (SAW-2015-FLI-3)
  • Deutsche Forschungsgemeinschaft (GRK1715/1, MO1421/2-1)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
  • Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
Keywords
inflammaging, peripheral nerve regeneration, Schwann cells, Schwann cell dedifferentiation, macrophage infiltration, eotaxin, MCP-1, chronic inflammation, sciatic nerve injury, hyperinflammation, anti-inflammatory therapy, neuropathy
MeSH terms
Aging, Animals, Anti-Inflammatory Agents, Aspirin, Ganglia, Spinal, Inflammation, Mice, Inbred C57BL, Myelin Sheath, Nerve Crush, Nerve Regeneration, Peripheral Nerves, Schwann Cells, Sciatic Nerve, Chemokine CCL11, Peripheral Nerve Injuries

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review