Chitinase 3-like 1 is neurotoxic in primary cultured neurons
Open accessAbstract
Chitinase 3-like 1 (CHI3L1) is known to play a role as prognostic biomarker in the early stages of multiple sclerosis (MS), and patients with high cerebrospinal fluid CHI3L1 levels have an increased risk for the development of neurological disability. Here, we investigated its potential neurotoxic effect by adding recombinant CHI3L1 in vitro to primary cultures of mouse cortical neurons and evaluating both neuronal functionality and survival by immunofluorescence. CHI3L1 induced a significant neurite length retraction after 24 and 48 hours of exposure and significantly reduced neuronal survival at 48 hours. The cytotoxic effect of CHI3L1 was neuron-specific and was not observed in mouse immune or other central nervous system cells. These results point to a selective neurotoxic effect of CHI3L1 in vitro and suggest a potential role of CHI3L1 as therapeutic target in MS patients.
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.
Integrity signals
Registry
Cites
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.
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?
An astrocyte cluster associated with COVID-19 is marked by inflammation and astrogliosis genes such as IFITM3 and GFAP, and by upregulated CHI3L1.
“we uncovered an astrocyte cluster associated with COVID-19 that is marked by established inflammation and astrogliosis genes (such as IFITM3 and GFAP) and upregulated expression of the secreted neurotoxic factor chitinase 3-like 1 (CHI3L1)39”
From Dysregulation of brain and choroid plexus cell types in severe COVID-19 (2021) · cites this paper as [39]
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
Axonal transection in the lesions of multiple sclerosis
Trapp, B. D., Peterson, J., Ransohoff, R. M., Rudick, R., Mörk, S., & Bö, L. (1998) · New England Journal of Medicine · doi:10.1056/nejm199801293380502 · Cited by 4,029 · see citing works
Influence of dendritic structure on firing pattern in model neocortical neurons
Mainen, Z. F., & Sejnowski, T. J. (1996) · Nature · doi:10.1038/382363a0 · Cited by 1,231 · see citing works
Acute axonal injury in multiple sclerosis: Correlation with demyelination and inflammation
Bitsch, A. (2000) · Brain · doi:10.1093/brain/123.6.1174 · Cited by 898 · see citing works
Renkema, G. H., Boot, R. G., Au, F. L., Donker‐Koopman, W. E., Strijland, A., Muijsers, A. O., Hřebı́ček, M., & Aerts, J. M. F. G. (1998) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1998.2510504.x · Cited by 403 · see citing works
Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis
Comabella, M., Fernández, M., Martinꝉ, R., Rivera-Vallvé, S., Borràs, E., Chiva, C., Julià, E., Rovira, À., Cantó, E., Alvarez-Cermeño, J. C., et al. (2010) · Brain · doi:10.1093/brain/awq035 · Cited by 302 · see citing works
Self-citationIn vivo CHI3L1 (YKL-40) expression in astrocytes in acute and chronic neurological diseases
Bonneh‐Barkay, D., Wang, G., Starkey, A., Hamilton, R. L., & Wiley, C. A. (2010) · Journal of Neuroinflammation · doi:10.1186/1742-2094-7-34 · Cited by 293 · see citing works
NeuriteTracer: A novel ImageJ plugin for automated quantification of neurite outgrowth
Pool, M., Thiemann, J., Bar‐Or, A., & Fournier, A. E. (2007) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2007.08.029 · Cited by 254 · see citing works
Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes
Cantó, E., Tintoré, M., Villar, L. M., Costa, C., Nurtdinov, R., Álvarez-Cermeño, J. C., Arrambide, G., Reverter, F., Deisenhammer, F., Hegen, H., et al. (2015) · Brain · doi:10.1093/brain/awv017 · Cited by 193 · see citing works
Self-citationProfiling the genes affected by pathogenic TDP ‐43 in astrocytes
Huang, C., Huang, B., Bi, F., Yan, L. H., Tong, J., Huang, J., Xia, X., & Zhou, H. (2014) · Journal of Neurochemistry · doi:10.1111/jnc.12660 · Cited by 40 · see citing works
Neurite Growth Patterns Leading to Functional Synapses in an Identified Embryonic Neuron
Reese, D., & Drapeau, P. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-15-05652.1998 · Cited by 22 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Dysregulation of brain and choroid plexus cell types in severe COVID-19
Yang, A. C., Kern, F., Losada, P. M., Agam, M. R., Maat, C. A., Schmartz, G. P., Fehlmann, T., Stein, J. A., Schaum, N., Lee, D. P., et al. (2021) · Nature · doi:10.1038/s41586-021-03710-0 · Cited by 620 · see citing works
Connolly, K., Lehoux, M., O’Rourke, R., Assetta, B., Erdemir, G. A., Elias, J. A., Lee, C. G., & Huang, Y. A. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12612 · Cited by 142 · see citing works
Diversity of Reactive Astrogliosis in CNS Pathology: Heterogeneity or Plasticity?
Moulson, A. J., Squair, J. W., Franklin, R. J. M., Tetzlaff, W., & Assinck, P. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.703810 · Cited by 90 · see citing works
Role of Chitinase 3–like 1 as a Biomarker in Multiple Sclerosis
Floro, S., Carandini, T., Pietroboni, A. M., Riz, M. A. D., Scarpini, E. A., & Galimberti, D. (2022) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000001164 · Cited by 72 · see citing works
Neuroinflammation in neurodegeneration via microbial infections
Tran, V. T. A., Lee, L. P., & Cho, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.907804 · Cited by 68 · see citing works
Mwale, P. F., Hsieh, C.-T., Yen, T.-L., Jan, J.-S., Taliyan, R., Yang, C.-H., & Yang, W.-B. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00801-8 · Cited by 47 · see citing works
Potential Role of CHI3L1+ Astrocytes in Progression in MS
Cubas-Núñez, L., Gil‐Perotín, S., Castillo-Villalba, J., López, V. P., Tarazona, L. R. S., Gasqué-Rubio, R., Carratalà‐Boscà, S., Alcalà-Vicente, C., Miralles, F. C. P., Lassmann, H., et al. (2021) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000000972 · Cited by 50 · see citing works
“The CHI3L1 protein induced cytotoxicity in cultured neurons in vitro through a mechanism that is as yet unknown.(40) Moreover, CHI3L1 levels increase in neurodegenerative diseases like Alzheimer disease as patients deteriorate, and high levels of this protein in amyotrophic lateral sclerosis imply a more accelerated d…”
BackgroundSadeghi, I., Gispert, J. D., Palumbo, E., Muñoz-Aguirre, M., Wucher, V., D’Argenio, V., Santpere, G., Navarro, A., Guigó, R., & Vilor‐Tejedor, N. (2022) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2022.08.037 · Cited by 39 · see citing works
Zeng, X., Cheung, S. K. K., Shi, M., Or, P. M. Y., Li, Z., Liu, J. Y. H., Ho, W. L.-H., Liu, T., Lu, K., Rudd, J. A., et al. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02970-z · Cited by 27 · see citing works
“…to be neuroprotective and/or anti-inflammatory in traumatic brain injury [38], experimental autoimmune encephalomyelitis [39], and bacterial infection [40]; whereas others have observed attenuated cell viability and retracted neurites in primary cortical neurons treated with YKL-40 [41, 42].”
BackgroundCombination protein biomarkers predict multiple sclerosis diagnosis and outcomes
Kodosaki, E., Watkins, W. J., Loveless, S., Kreft, K. L., Richards, A., Anderson, V. M., Hurler, L., Robertson, N. P., Zelek, W. M., & Tallantyre, E. C. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03036-4 · Cited by 28 · see citing works
“Chitinase-3-like-1 is a marker of macrophage and astrocyte activation and is potentially neurotoxic [19].”
BackgroundMasvekar, R. R., Phillips, J., Komori, M., Wu, T., & Bielekova, B. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.649876 · Cited by 24 · see citing works
Cerebrospinal Fluid Chitinases as Biomarkers for Amyotrophic Lateral Sclerosis
Costa, J., Gromicho, M., Pronto‐Laborinho, A. C., Almeida, C., Gomes, R. A., Guerreiro, A. C. L., Oliva, A., Pinto, S., & de Carvalho, M. A. (2021) · Diagnostics · doi:10.3390/diagnostics11071210 · Cited by 23 · see citing works
“In line with this, CHI3L1 was found to be neurotoxic towards cortical neurons but not immune cells [43].”
BackgroundLiu, D., Hu, X., Ding, X., Li, M., & Ding, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413437 · Cited by 20 · see citing works
“Mechanistically, Chi3l1 can exert cytotoxic effects by inducing neurite length retraction and reducing neuronal survival only in neurons but not in other central nervous system cells, indicating that Chi3l1 is a potential therapeutic target for MS patients [197].”
Salabi, F., & Jafari, H. (2022) · BMC Genomics · doi:10.1186/s12864-022-08866-1 · Cited by 18 · see citing works
An Update on Diagnostic Laboratory Biomarkers for Multiple Sclerosis
Kaisey, M., Lashgari, G., Fert‐Bober, J., Ontaneda, D., Solomon, A. J., & Sicotte, N. L. (2022) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-022-01227-1 · Cited by 16 · see citing works
The chitinases as biomarkers in immune-mediate diseases
Francesco, A. M. D., Verrecchia, E., Manna, S., Urbani, A., & Manna, R. (2022) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2022-0767 · Cited by 15 · see citing works
Whitsitt, Q. A., Saxena, A., Patel, B., Evans, B. M., Hunt, B., & Purcell, E. K. (2024) · Journal of Neural Engineering · doi:10.1088/1741-2552/ad5936 · Cited by 22 · see citing works
“…DE in the region 300 µ ms from the implant site relative to naïve tissue included markers related to astrocyte reactivity ( Lcn2 [59, 60], Chi3L1 [61, 62]), neurodegeneration( Hspb1, Lcn2 ) [59, 60, 63], intracerebral haemorrhage ( Mt2a [64]), and neuroinflammation ( C1 , C3 , Spp1 [65, 66])).”
BackgroundAn Association of Chitinase-3 Like-Protein-1 With Neuronal Deterioration in Multiple Sclerosis
Ahmad, I., Wergeland, S., Oveland, E., & Bø, L. (2023) · ASN NEURO · doi:10.1177/17590914231198980 · Cited by 12 · see citing works
“The expression and/or secretion of CHI3L1 may be neurotoxic, as CHI3L1 concentrations similar to those measured in the CSF from active MS patients were mildly neurotoxic to primary cultured neurons in vitro (Matute-Blanch et al., 2020).”
BackgroundA sex-stratified analysis of neuroimmune gene expression signatures in Alzheimer’s disease brains
Sanfilippo, C., Castrogiovanni, P., Vinciguerra, M., Imbesi, R., Ulivieri, M., Fazio, F., Blennow, K., Zetterberg, H., & Rosa, M. D. (2022) · GeroScience · doi:10.1007/s11357-022-00664-7 · Cited by 11 · see citing works
“It has been shown that CHI3L1 plays a direct role in neurons [89].”
BackgroundThe Heterogeneous Multiple Sclerosis Lesion: How Can We Assess and Modify a Degenerating Lesion?
Ellen, O., Ye, S., Nheu, D., Dass, M., Pagnin, M., Öztürk, E., Theotokis, P., Grigoriadis, N., & Petratos, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241311112 · Cited by 10 · see citing works
Ruiz, V. Y., Calderon, T. M., León‐Rivera, R., Chilunda, V., Zhang, J., & Berman, J. W. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1475480 · Cited by 9 · see citing works
“It is also neurotoxic (81, 82) and inhibits neurogenesis (83, 84), suggesting its role in neuroin fl ammation and neurodegeneration.”
Plasma CHI3L1 associates with brain volume loss and glial activation in multiple sclerosis
Ahola, V., Saraste, M., Nylund, M., Matilainen, M., Luoma, A., Vuorimaa, A., Lehto, J., Laaksonen, S., Brockmann, E., Kuhle, J., et al. (2025) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2025-336063 · Cited by 9 · see citing works
“13 Furthermore, it has been stated that CHI3L1 is cytotoxic to neurons in vitro 14 and impairs neurogenesis in vivo.”
Yilmazer‐Hanke, D., Alami, N. O., Fang, L., Klotz, S., Kovács, G. G., Pankratz, H., Weis, J., Katona, I., Scheuerle, A., Streit, W. J., et al. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.10.018 · Cited by 6 · see citing works
Kušnierová, P., Revendová, K. Ž., Karasova, K., Zeman, D., Bunganic, R., Hradílek, P., Volný, O., Ganesh, A., Kovacova, I., & Stejskal, D. (2024) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2024.105915 · Cited by 5 · see citing works
Chitinase-3-like protein 1: Features and applications as a biomarker in traumatic brain injury
Carabias, C. S., & Lagares, A. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-823347-4.00009-9 · Cited by 4 · see citing works
Prognostic performance of serum YKL-40 for one-year clinical outcomes in acute ischemic stroke
Shi, G., Li, M., Yan, E., Wang, M., Gong, P., Wang, X., Lu, J., Wu, W., Xue, S., Zhou, J., et al. (2023) · Aging · doi:10.18632/aging.204553 · Cited by 4 · see citing works
Riggins, T. E., Whitsitt, Q. A., Saxena, A., Hunter, E., Hunt, B., Thompson, C. H., Moore, M. G., & Purcell, E. K. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.01.06.522870 · Cited by 3 · see citing works
Proteins secreted by brain arteriolar smooth muscle cells are instructive for neural development
Li, X., Zhou, L., Zhang, X., Jin, Y., Zhao, B., Zhang, D., Xi, C., Ruan, J., Zhu, Z., & Jia, J. (2022) · Molecular Brain · doi:10.1186/s13041-022-00983-y · Cited by 2 · see citing works
Shi, G., Li, M., Yan, E., Zhou, J., Wang, M., Gong, P., Wang, X., Lu, J., Wu, W., Xue, S., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-2080278/v1 · Cited by 1 · see citing works
Combination protein biomarkers predict multiple sclerosis diagnosis and outcomesPreprint
Kodosaki, E., Watkins, W. J., Loveless, S., Kreft, K. L., Richards, A., Anderson, V. M., Hurler, L., Robertson, N. P., Zelek, W. M., & Tallantyre, E. C. (2023) · Research Square · doi:10.21203/rs.3.rs-3425337/v1 · Cited by 1 · see citing works
Salabi, F., & Jafari, H. (2022) · Research Square · doi:10.21203/rs.3.rs-1285424/v1
Bărcuţean, L., Huţanu, A., Andone, S. R., Maier, S., & Bălașa, R. (2023) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527322666230609164534
Bubeníková, A., Máčová, L., Skalický, P., Mládek, A., & Bradáč, O. (2023) · Springer eBooks · doi:10.1007/978-3-031-36522-5_15
Chitinase 3‐like 1 is neurotoxic in multiple sclerosis patient‐derived cortical neurons
Pinteac, R., Soriano, J., Matute‐Blanch, C., Lizcano, J. M., Duarri, A., Malhotra, S., Eixarch, H., Comellas, G. L., Montalbán, X., & Comabella, M. (2024) · Clinical and Translational Medicine · doi:10.1002/ctm2.70125
Self-citationKodosaki, E., Watkins, W. J., Loveless, S., Kreft, K. L., Richards, A., Anderson, V. M., Hurler, L., Robertson, N. P., Zelek, W. M., & Tallantyre, E. C. (2024) · Figshare · doi:10.6084/m9.figshare.25239408
Salabi, F., & Jafari, H. (2022) · Figshare · doi:10.6084/m9.figshare.21069342
Zeng, X., Cheung, S. K. K., Shi, M., Or, P. M. Y., Li, Z., Liu, J. Y. H., Ho, W. L.-H., Liu, T., Lu, K., Rudd, J. A., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26648808
The role of YKL-40 in Alzheimer’s disease pathology and drug targeting
Sha, Y., Fu, H., Lu, K., Wang, G., & Wang, Y. (2026) · PeerJ · doi:10.7717/peerj.21361
- Authors
- Matute-Blanch, C., Calvo-Barreiro, L., Carballo-Carbajal, I., Gonzalo, R., Sanchez, A., Vila, M., Montalban, X., & Comabella, M.
- Affiliations
- Vall d'Hebron Institut de Recerca (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Universitat Autònoma de Barcelona (ES)
- Corresponding author
- Comabella, Manuel
- Venue
- Scientific Reports
- Published
- 2020-04-28
- Volume
- 10
- Issue
- 1
- Pages
- 7118-7118
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC7188887
- OpenAlex
- W3020413154
- Cited by
- 38
- References
- 10
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 7 · 2023: 8 · 2022: 14 · 2021: 5
- FWCI
- 2.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
- Funders
- Generalitat de Catalunya
- Ministerio de Ciencia e Innovación
- Red Española de Esclerosis Múltiple
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Studies on Chitinases and Chitosanases
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- YKL-40, neurotoxicity, multiple sclerosis, cortical neurons, neurite retraction, neuronal survival, cerebrospinal fluid biomarkers, therapeutic target
- MeSH terms
- Chitinase-3-Like Protein 1, Animals, Cell Survival, Cells, Cultured, Humans, Multiple Sclerosis, Neurons, Recombinant Proteins, Biomarkers, 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
