CoChat
Sign Up
Cited by 33Multiple Sclerosis Research StudiesNeuroinflammation and Neurodegeneration MechanismsT-cell and B-cell Immunology

Astrocyte-Derived Pleiotrophin Mitigates Late-Stage Autoimmune CNS Inflammation

Open access
Linnerbauer, Mathias, Lößlein, Lena, Farrenkopf, Daniel, Vandrey, Oliver, Tsaktanis, Thanos, Naumann, Ulrike, Rothhammer, Veit·2022·Frontiers in Immunology
DOI 10.3389/fimmu.2021.800128PMC PMC8762329
Open this paper in CoChat — free account

Abstract

Astrocytes are the most abundant glial cells in the central nervous system (CNS) with the capacity to sense and react to injury and inflammatory events. While it has been widely documented that astrocytes can exert tissue-degenerative functions, less is known about their protective and disease-limiting roles. Here, we report the upregulation of pleiotrophin (PTN) by mouse and human astrocytes in multiple sclerosis (MS) and its preclinical model experimental autoimmune encephalomyelitis (EAE). Using CRISPR-Cas9-based genetic perturbation systems, we demonstrate in vivo that astrocyte-derived PTN is critical for the recovery phase of EAE and limits chronic CNS inflammation. PTN reduces pro-inflammatory signaling in astrocytes and microglia and promotes neuronal survival following inflammatory challenge. Finally, we show that intranasal administration of PTN during the late phase of EAE successfully reduces disease severity, making it a potential therapeutic candidate for the treatment of progressive MS, for which existing therapies are limited.

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 · 10.3389/fimmu.2021.800128

Cites

7 of 7 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?

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: 51

  1. [2]Wheeler MA Quintana FJ. Regulation of Astrocyte Functions in Multiple Sclerosis. Cold Spring Harb Perspect Med (2019) 9: a029009. doi: 10.1101/cshperspect.a029009 29358321 PMC6314073 · DOI
  2. [5]Linnerbauer M Rothhammer V. Protective Functions of Reactive Astrocytes Following Central Nervous System Insult. Front Immunol (2020) 11: 3389/fimmu.2020.573256. doi: 10.3389/fimmu.2020.573256 PMC7561408 33117368 · DOI
  3. [6]Sanmarco LM Wheeler MA Gutiérrez-Vázquez C Polonio CM Linnerbauer M Pinho-Ribeiro FA. Gut-Licensed Ifnγ + NK Cells Drive LAMP1 + TRAIL + Anti-Inflammatory Astrocytes. Nature (2021) 590: 473–9. doi: 10.1038/s41586-020-03116-4 PMC8039910 33408417 · DOI · Paper page
  4. [7]Wheeler MA Clark IC Tjon EC Li Z Zandee SEJ Couturier CP. MAFG-Driven Astrocytes Promote CNS Inflammation. Nature (2020) 578: 593–9. doi: 10.1038/s41586-020-1999-0 PMC8049843 32051591 · DOI · Paper page
  5. [8]Zamanian JL Xu L Foo LC Nouri N Zhou L Giffard RG. Genomic Analysis of Reactive Astrogliosis. J Neurosci Off J Soc Neurosci (2012) 32: 6391–410. doi: 10.1523/JNEUROSCI.6221-11.2012 PMC3480225 22553043 · DOI · Paper page
  6. [10]Papadimitriou E Pantazaka E Castana P Tsalios T Polyzos A Beis D. Pleiotrophin and Its Receptor Protein Tyrosine Phosphatase Beta/Zeta as Regulators of Angiogenesis and Cancer. Biochim Biophys Acta (2016) 1866: 252–65. doi: 10.1016/j.bbcan.2016.09.007 27693125 · DOI
  7. [11]Silos-Santiago I Yeh HJ Gurrieri MA Guillerman RP Li YS Wolf J. Localization of Pleiotrophin and Its mRNA in Subpopulations of Neurons and Their Corresponding Axonal Tracts Suggests Important Roles in Neural-Glial Interactions During Development and in Maturity. J Neurobiol (1996) 31: 283–96. doi: 10.1002/(SICI)1097-4695(199611)31:3<283::AID-NEU2>3.0.CO;2-6 8910787 · DOI
  8. [12]Böhlen P Kovesdi I. HBNF and MK, Members of a Novel Gene Family of Heparin-Binding Proteins With Potential Roles in Embryogenesis and Brain Function. Prog Growth Factor Res (1991) 3: 143–57. doi: 10.1016/s0955-2235(05)80005-5 1773041 · DOI
  9. [13]Fang W Hartmann N Chow DT Riegel AT Wellstein A. Pleiotrophin Stimulates Fibroblasts and Endothelial and Epithelial Cells and Is Expressed in Human Cancer. J Biol Chem (1992) 267: 25889–97. doi: 10.1016/S0021-9258(18)35692-8 1464602 · DOI
  10. [14]Marchionini DM Lehrmann E Chu Y He B Sortwell CE Becker KG. Role of Heparin Binding Growth Factors in Nigrostriatal Dopamine System Development and Parkinson’s Disease. Brain Res (2007) 1147: 77– 88. doi: 10.1016/j.brainres.2007.02.028 17368428 · DOI · Paper page
  11. [16]Yeh HJ He YY Xu J Hsu CY Deuel TF. Upregulation of Pleiotrophin Gene Expression in Developing Microvasculature, Macrophages, and Astrocytes After Acute Ischemic Brain Injury. J Neurosci Off J Soc Neurosci (1998) 18: 3699–707. doi: 10.1523/JNEUROSCI.18-10-03699.1998 PMC6793139 9570800 · DOI
  12. [17]García-Pérez D Laorden ML Milanés MV. Regulation of Pleiotrophin, Midkine, Receptor Protein Tyrosine Phosphatase β/ζ, and Their Intracellular Signaling Cascades in the Nucleus Accumbens During Opiate Administration. Int J Neuropsychopharmacol (2016) 19: 15066–75. doi: 10.1093/ijnp/pyv077 PMC4772269 26164717 · DOI
  13. [18]Gramage E Rossi L Granado N Moratalla R Herradón G. Genetic Inactivation of Pleiotrophin Triggers Amphetamine-Induced Cell Loss in the Substantia Nigra and Enhances Amphetamine Neurotoxicity in the Striatum. Neuroscience (2010) 170: 308–16. doi: 10.1016/j.neuroscience.2010.06.078 20620199 · DOI
  14. [19]Le Grevès P. Pleiotrophin Gene Transcription in the Rat Nucleus Accumbens Is Stimulated by an Acute Dose of Amphetamine. Brain Res Bull (2005) 65: 529–32. doi: 10.1016/j.brainresbull.2005.03.010 15862925 · DOI
  15. [21]Tusher VG Tibshirani R Chu G. Significance Analysis of Microarrays Applied to the Ionizing Radiation Response. Proc Natl Acad Sci (2001) 98: 5116–21. doi: 10.1073/pnas.091062498 PMC33173 11309499 · DOI · Paper page
  16. [22]Nikolakopoulou AM Montagne A Kisler K Dai Z Wang Y Huuskonen MT. Pericyte Loss Leads to Circulatory Failure and Pleiotrophin Depletion Causing Neuron Loss. Nat Neurosci (2019) 22: 1089–98. doi: 10.1038/s41593-019-0434-z PMC6668719 31235908 · DOI
  17. [23]Miao J Ding M Zhang A Xiao Z Qi W Luo N. Pleiotrophin Promotes Microglia Proliferation and Secretion of Neurotrophic Factors by Activating Extracellular Signal-Regulated Kinase 1/2 Pathway. Neurosci Res (2012) 74: 269–76. doi: 10.1016/j.neures.2012.09.001 23000062 · DOI
  18. [24]Satoh J Kuroda Y. Differing Effects of Ifnβ vs Ifnγ in MS: Gene Expression in Cultured Astrocytes. Neurology (2001) 57: 681–5. doi: 10.1212/WNL.57.4.681 11524479 · DOI
  19. [25]Takeda A Onodera H Sugimoto A Itoyama Y Kogure K Rauvala H. Induction of Heparin-Binding Growth-Associated Molecule Expression in Reactive Astrocytes Following Hippocampal Neuronal Injury. Neuroscience (1995) 68: 57– 64. doi: 10.1016/0306-4522(95)00110-5 7477935 · DOI
  20. [26]Sandelin A Alkema W Engström P Wasserman WW Lenhard B. JASPAR: An Open-Access Database for Eukaryotic Transcription Factor Binding Profiles. Nucleic Acids Res (2004) 32: D91–94. doi: 10.1093/nar/gkh012 PMC308747 14681366 · DOI
  21. [27]Rothhammer V Mascanfroni ID Bunse L Takenaka MC Kenison JE Mayo L. Type I Interferons and Microbial Metabolites of Tryptophan Modulate Astrocyte Activity and CNS Inflammation via the Aryl Hydrocarbon Receptor. Nat Med (2016) 22: 586–97. doi: 10.1038/nm.4106 PMC4899206 27158906 · DOI · Paper page
  22. [28]Rothhammer V Kenison JE Li Z Tjon E Takenaka MC Chao C-C. Aryl Hydrocarbon Receptor Activation in Astrocytes by Laquinimod Ameliorates Autoimmune Inflammation in the CNS. Neurol - Neuroimmunol Neuroinflamm (2021) 8: e946. doi: 10.1212/NXI.0000000000000946 33408169 PMC7862099 · DOI
  23. [29]Rothhammer V Kenison JE Tjon E Takenaka MC de Lima KA Borucki DM. Sphingosine 1-Phosphate Receptor Modulation Suppresses Pathogenic Astrocyte Activation and Chronic Progressive CNS Inflammation. Proc Natl Acad Sci (2017) 114: 2012–7. doi: 10.1073/pnas.1615413114 PMC5338419 28167760 · DOI
  24. [30]Iwasaki S Yamamoto S Sano N Tohyama K Kosugi Y Furuta A. Direct Drug Delivery of Low-Permeable Compounds to the Central Nervous System Via Intranasal Administration in Rats and Monkeys. Pharm Res (2019) 36: 76. doi: 10.1007/s11095-019-2613-8 30937626 · DOI
  25. [31]Ross TM Martinez PM Renner JC Thorne RG Hanson LR Frey WH. Intranasal Administration of Interferon Beta Bypasses the Blood-Brain Barrier to Target the Central Nervous System and Cervical Lymph Nodes: A Non-Invasive Treatment Strategy for Multiple Sclerosis. J Neuroimmunol (2004) 151: 66– 77. doi: 10.1016/j.jneuroim.2004.02.011 15145605 · DOI · Paper page
  26. [32]Kuboyama K Fujikawa A Suzuki R Noda M. Inactivation of Protein Tyrosine Phosphatase Receptor Type Z by Pleiotrophin Promotes Remyelination Through Activation of Differentiation of Oligodendrocyte Precursor Cells. J Neurosci (2015) 35: 12162–71. doi: 10.1523/jneurosci.2127-15.2015 PMC6605312 26338327 · DOI
  27. [33]Liu X Mashour GA Webster HD Kurtz A. Basic FGF and FGF Receptor 1 Are Expressed in Microglia During Experimental Autoimmune Encephalomyelitis: Temporally Distinct Expression of Midkine and Pleiotrophen. Glia (1998) 24: 390–7. doi: 10.1002/(SICI)1098-1136(199812)24:4<390::AID-GLIA4>3.0.CO;2-1 9814819 · DOI
  28. [34]Chen H Campbell RA Chang Y Li M Wang CS Li J. Pleiotrophin Produced by Multiple Myeloma Induces Transdifferentiation of Monocytes Into Vascular Endothelial Cells: A Novel Mechanism of Tumor-Induced Vasculogenesis. Blood (2009) 113: 1992– 2002. doi: 10.1182/blood-2008-02-133751 19060246 PMC2651013 · DOI
  29. [35]Fernández-Calle R Vicente-Rodríguez M Gramage E Pita J Pérez-García C Ferrer-Alcón M. Pleiotrophin Regulates Microglia-Mediated Neuroinflammation. J Neuroinflamm (2017) 14: 46. doi: 10.1186/s12974-017-0823-8 PMC5336633 28259175 · DOI
  30. [36]Sharifi BG Zeng Z Wang L Song L Chen H Qin M. Pleiotrophin Induces Transdifferentiation of Monocytes Into Functional Endothelial Cells. Arterioscler Thromb Vasc Biol (2006) 26: 1273–80. doi: 10.1161/01.ATV.0000222017.05085.8e PMC3579570 16614316 · DOI
  31. [37]Qin EY Cooper DD Abbott KL Lennon J Nagaraja S Mackay A. Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma. Cell (2017) 170: 845– 59.e19. doi: 10.1016/j.cell.2017.07.016 28823557 PMC5587159 · DOI
  32. [38]Shi Y Ping Y-F Zhou W He Z-C Chen C Bian B.-S.-J.. Tumour-Associated Macrophages Secrete Pleiotrophin to Promote PTPRZ1 Signalling in Glioblastoma Stem Cells for Tumour Growth. Nat Commun (2017) 8: 15080. doi: 10.1038/ncomms15080 28569747 PMC5461490 · DOI
  33. [39]De Stefano N Matthews PM Filippi M Agosta F De Luca M Bartolozzi ML. Evidence of Early Cortical Atrophy in MS: Relevance to White Matter Changes and Disability. Neurology (2003) 60: 1157–62. doi: 10.1212/01.wnl.0000055926.69643.03 12682324 · DOI
  34. [40]Magliozzi R Howell O Vora A Serafini B Nicholas R Puopolo M. Meningeal B-Cell Follicles in Secondary Progressive Multiple Sclerosis Associate With Early Onset of Disease and Severe Cortical Pathology. Brain J Neurol (2007) 130: 1089–104. doi: 10.1093/brain/awm038 17438020 · DOI
  35. [41]Sanfilipo MP Benedict RHB Weinstock-Guttman B Bakshi R. Gray and White Matter Brain Atrophy and Neuropsychological Impairment in Multiple Sclerosis. Neurology (2006) 66: 685–92. doi: 10.1212/01.wnl.0000201238.93586.d9 16534104 · DOI
  36. [43]Comi G Dadon Y Sasson N Steinerman JR Knappertz V Vollmer TL. CONCERTO: A Randomized, Placebo-Controlled Trial of Oral Laquinimod in Relapsing-Remitting Multiple Sclerosis. Mult Scler J (2021) 13524585211032804. doi: 10.1177/13524585211032803 34378456 · DOI
  37. [44]Rothhammer V Borucki DM Garcia Sanchez MI Mazzola MA Hemond CC Regev K. Dynamic Regulation of Serum Aryl Hydrocarbon Receptor Agonists in MS. Neurol Neuroimmunol Neuroinflamm (2017) 4: e359. doi: 10.1212/NXI.0000000000000359 28642887 PMC5473958 · DOI
  38. [45]Tsaktanis T Beyer T Nirschl L Linnerbauer M Grummel V Bussas M. Aryl Hydrocarbon Receptor Plasma Agonist Activity Correlates With Disease Activity in Progressive MS. Neurol - Neuroimmunol Neuroinflamm (2021) 8. doi: 10.1212/NXI.0000000000000933 PMC7768947 33361385 · DOI
  39. [46]Dong Y Fischer R Naudé PJW Maier O Nyakas C Duffey M. Essential Protective Role of Tumor Necrosis Factor Receptor 2 in Neurodegeneration. Proc Natl Acad Sci (2016) 113: 12304–9. doi: 10.1073/pnas.1605195113 PMC5087045 27791020 · DOI
  40. [47]Frei K Eugster H-P Bopst M Constantinescu CS Lavi E Fontana A. Tumor Necrosis Factor α and Lymphotoxin α Are Not Required for Induction of Acute Experimental Autoimmune Encephalomyelitis. J Exp Med (1997) 185: 2177–82. doi: 10.1084/jem.185.12.2177 PMC2196356 9182689 · DOI
  41. [48]Liu J Marino MW Wong G Grail D Dunn A Bettadapura J. TNF Is a Potent Anti-Inflammatory Cytokine in Autoimmune-Mediated Demyelination. Nat Med (1998) 4: 78– 83. doi: 10.1038/nm0198-078 9427610 · DOI
  42. [49]Probert L. TNF and Its Receptors in the CNS: The Essential, the Desirable and the Deleterious Effects. Neuroscience (2015) 302: 2– 22. doi: 10.1016/j.neuroscience.2015.06.038 26117714 · DOI
  43. [50]Turrin NP Rivest S. Tumor Necrosis Factor α But Not Interleukin 1β Mediates Neuroprotection in Response to Acute Nitric Oxide Excitotoxicity. J Neurosci (2006) 26: 143–51. doi: 10.1523/JNEUROSCI.4032-05.2006 PMC6674332 16399681 · DOI
  44. [51]Zhao S Jiang J Jing Y Liu W Yang X Hou X. The Concentration of Tumor Necrosis Factor-α Determines Its Protective or Damaging Effect on Liver Injury by Regulating Yap Activity. Cell Death Dis (2020) 11: 1– 13. doi: 10.1038/s41419-020-2264-z 31988281 PMC6985193 · DOI
  45. [52]Kassiotis G Pasparakis M Kollias G Probert L. TNF Accelerates the Onset But Does Not Alter the Incidence and Severity of Myelin Basic Protein-Induced Experimental Autoimmune Encephalomyelitis. Eur J Immunol (1999) 29: 774–80. doi: 10.1002/(SICI)1521-4141(199903)29:03<774::AID-IMMU774>3.0.CO;2-T 10092079 · DOI
  46. [54]Papazian I Tsoukala E Boutou A Karamita M Kambas K Iliopoulou L. Fundamentally Different Roles of Neuronal TNF Receptors in CNS Pathology: TNFR1 and Ikkβ Promote Microglial Responses and Tissue Injury in Demyelination While TNFR2 Protects Against Excitotoxicity in Mice. J Neuroinflamm (2021) 18: 222. doi: 10.1186/s12974-021-02200-4 PMC8466720 34565380 · DOI
  47. [55]Raphael I Gomez-Rivera F Raphael RA Robinson RR Nalawade S Forsthuber TG. TNFR2 Limits Proinflammatory Astrocyte Functions During EAE Induced by Pathogenic DR2b-Restricted T Cells. JCI Insight (2019) 4: 132527. doi: 10.1172/jci.insight.132527 31852844 PMC6975265 · DOI
  48. [56]Clark IC Gutiérrez-Vázquez C Wheeler MA Li Z Rothhammer V Linnerbauer M. Barcoded Viral Tracing of Single-Cell Interactions in Central Nervous System Inflammation. Science (2021) 372: eabf1230. doi: 10.1126/science.abf1230 33888612 PMC8157482 · DOI · Paper page
  49. [57]Fornes O Castro-Mondragon JA Khan A van der Lee R Zhang X Richmond PA. JASPAR 2020: Update of the Open-Access Database of Transcription Factor Binding Profiles. Nucleic Acids Res (2020) 48: D87–92. doi: 10.1093/nar/gkz1001 PMC7145627 31701148 · DOI · Paper page
  50. [58]Chao C-C Gutiérrez-Vázquez C Rothhammer V Mayo L Wheeler MA Tjon EC. Metabolic Control of Astrocyte Pathogenic Activity via Cpla2-MAVS. Cell (2019) 179: 1483– 98.e22. doi: 10.1016/j.cell.2019.11.016 31813625 PMC6936326 · DOI
  51. [59]Rothhammer V Borucki DM Tjon EC Takenaka MC Chao C-C Ardura-Fabregat A. Microglial Control of Astrocytes in Response to Microbial Metabolites. Nature (2018) 557: 724–8. doi: 10.1038/s41586-018-0119-x PMC6422159 29769726 · DOI · Paper page

Cited by

Sorted by citations

Authors
Linnerbauer, M., Lößlein, L., Farrenkopf, D., Vandrey, O., Tsaktanis, T., Naumann, U., & Rothhammer, V.
Affiliations
Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
Corresponding author
Rothhammer, Veit
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2022-01-03
Volume
12
Pages
800128-800128
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2021.800128
PMC
PMC8762329
OpenAlex
W4206233724
Cited by
33
References
7
Citations by year
2026: 2 · 2025: 12 · 2024: 8 · 2023: 10 · 2022: 1
FWCI
5.25
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion)
  • OPUS FAU (Kooperativer Bibliotheksverbund Berlin-Brandenburg (KOBV), on behalf of the Universitätsbibliothek Erlangen-Nürnberg) (submittedVersion, cc-by)
Funders
  • Deutsche Forschungsgemeinschaft (RO4866/4-1, RO4866/3-1, Project ID 408885537 - TRR 274, Project ID 261193037 - CRC 1181)
  • European Research Council (HICI 851693)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
pleiotrophin, astrocytes, multiple sclerosis, experimental autoimmune encephalomyelitis, neuroinflammation, neuroprotection, microglia, neuronal survival, intranasal drug delivery, neuroinflammation therapy
MeSH terms
Animals, Astrocytes, Carrier Proteins, Encephalomyelitis, Autoimmune, Experimental, Humans, Mice, Inbred C57BL, Cytokines, Mice

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