Extracellular Neuroleukin Enhances Neuroleukin Secretion From Astrocytes and Promotes Axonal Growth in vitro and in vivo
Open accessAbstract
Under pathological conditions in the central nervous system (CNS), including spinal cord injury, astrocytes show detrimental effects against neurons. It is also known that astrocytes sometimes exert beneficial effects, such as neuroprotection and secretion of axonal growth factors. If beneficial effects of astrocytes after injury could be induced, dysfunction of the injured CNS may improve. However, a way of promoting beneficial functions in astrocytes has not been elucidated. In the current study, we focused on neuroleukin (NLK), which is known to have axonal growth activities in neurons. Although NLK is secreted from astrocytes, the function of NLK in astrocytes is poorly understood. We aimed to clarify the mechanism of NLK secretion in astrocytes and the functional significance of secreted NLK from astrocytes. Stimulation of cultured astrocytes with recombinant NLK significantly elevated the secretion of NLK from astrocytes. Furthermore, astrocyte conditioned medium treated with NLK increased axonal density in cultured cortical neurons. Recombinant NLK itself directly increased axonal density in cultured neurons. These results indicated that NLK secreted from astrocytes acted as an axonal growth factor and that secretion was stimulated by extracellular NLK. To elucidate a direct binding molecule of NLK on astrocytes, drug affinity responsive target stability (DARTS) analysis was performed. A 78 kDa glucose regulated protein (GRP78) was identified as a receptor for NLK, which was related to the secretion of NLK from astrocytes. When NLK was injected into the lesion site of spinal cord injured mice, axonal density in the injured region was significantly increased and hindlimb motor function improved. These results suggested that NLK-GRP78 signalling was important for the beneficial effects of astrocytes. This study strengthens the potential of astrocytes for use as therapeutic targets in CNS traumatic injury.
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NLK may support survival of sensory and spinal neurons and stimulate axonal growth.
“may support survival of sensory and spinal neurons and stimulate axonal growth [10–13]”
From Cerebrospinal fluid levels of the neurotrophic factor neuroleukin are increased in early Alzheimer’s disease, but not in cerebral amyloid angiopathy (2021) · cites this paper as [13]
The Introduction (page unavailable) reports pro-survival effects of NLK in cultured sensory neurons, and the Results report increased axonal density in cultured cortical neurons and spinal-cord-injured mice. The paper does not report a survival effect specifically in spinal neurons, so that part of the claim is not established by our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn the extracellular space, NLK supports neuronal survival and stimulates axonal growth.
“In the extracellular space NLK supports neuronal survival and stimulates axonal growth [10–13]”
From Cerebrospinal fluid levels of the neurotrophic factor neuroleukin are increased in early Alzheimer’s disease, but not in cerebral amyloid angiopathy (2021) · cites this paper as [13]
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Cites
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971 · see citing works
Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue
Mccarthy, K., & de Vellis, J. (1980) · Journal of Cell Biology · doi:10.1083/jcb.85.3.890 · Cited by 3,915 · see citing works
Regeneration beyond the glial scar
Silver, J., & Miller, J. H. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1326 · Cited by 3,090 · see citing works
Basso, D., Fisher, L., Anderson, A., Jakeman, L., McTigue, D. M., & Popovich, P. (2006) · Journal of Neurotrauma · doi:10.1089/neu.2006.23.635 · Cited by 1,615 · see citing works
Target identification using drug affinity responsive target stability (DARTS)
Lomenick, B., Hao, R., Jonai, N., Chin, R., Aghajan, M., Warburton, S., Wang, J., Wu, R. P., Gómez, F., Loo, J. A., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910040106 · Cited by 1,113 · see citing works
Okada, S., Nakamura, M., Katoh, H., Miyao, T., Shimazaki, T., Ishii, K., Yamane, J., Yoshimura, A., Iwamoto, Y., Toyama, Y., et al. (2006) · Nature Medicine · doi:10.1038/nm1425 · Cited by 963 · see citing works
The contribution of astrocytes and microglia to traumatic brain injury
Karve, I. P., Taylor, J. M., & Crack, P. J. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13125 · Cited by 651 · see citing works
Ni, M., Zhang, Y., & Lee, A. S. (2011) · Biochemical Journal · doi:10.1042/bj20101569 · Cited by 544 · see citing works
Tumor cell autocrine motility factor.
Liotta, L. A., Mandler, R. N., Murano, G., Katz, D. A., Gordon, R. K., Chiang, P. K., & Schiffmann, E. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.10.3302 · Cited by 533 · see citing works
Dougherty, K. D., Dreyfus, C., & Black, I. (2000) · Neurobiology of Disease · doi:10.1006/nbdi.2000.0318 · Cited by 373 · see citing works
Shinozaki, Y., Shibata, K., Yoshida, K., Shigetomi, E., Gachet, C., Ikenaka, K., Tanaka, K. F., & Koizumi, S. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.04.047 · Cited by 341 · see citing works
Reactive Astrogliosis after Spinal Cord Injury—Beneficial and Detrimental Effects
Karimi-Abdolrezaee, S., & Billakanti, R. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8287-4 · Cited by 331 · see citing works
Gurney, M. E., Heinrich, S. P., Lee, M. R., & Yin, H.-S. (1986) · Science · doi:10.1126/science.3764429 · Cited by 331 · see citing works
Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide.
Watanabe, H., TAKEHANA, K., Date, M., Shinozaki, T., & Raz, A. (1996) · PubMed · Cited by 268 · see citing works
Lucarelli, G. T., Galleggiante, V., Rutigliano, M., Sanguedolce, F., Cagiano, S., Bufo, P., Lastilla, G., Maiorano, E., Ribatti, D., Giglio, A., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.3823 · Cited by 240 · see citing works
Kelber, J. A., Panopoulos, A. D., Shani, G., Booker, E. C., Belmonte, J. C. I., Vale, W., & Gray, P. C. (2009) · Oncogene · doi:10.1038/onc.2009.97 · Cited by 181 · see citing works
Purification of human tumor cell autocrine motility factor and molecular cloning of its receptor
Watanabe, H., Carmi, P., Hogan, V. A., Raz, T., Silletti, S., Nabi, I. R., & Raz, A. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)98859-9 · Cited by 178 · see citing works
Tohda, C., Urano, T., Umezaki, M., Nemere, I., & Kuboyama, T. (2012) · Scientific Reports · doi:10.1038/srep00535 · Cited by 167 · see citing works
Self-citationDeclèves, X., Régina, A., Laplanche, J., Roux, F. S., Boval, B., Launay, J., & Scherrmann, J. (2000) · Journal of Neuroscience Research · doi:10.1002/(sici)1097-4547(20000601)60:5 · Cited by 159 · see citing works
Molecular & Cellular Proteomics
(2021) · Molecular & Cellular Proteomics · doi:10.1074/mcp · Cited by 158 · see citing works
Niinaka, Y., Paku, S., Haga, A., Watanabe, H., & Raz, A. (1998) · PubMed · Cited by 142 · see citing works
Nerve Growth Factor in Glia and Inflammatory Cells of the Injured Rat Spinal Cord
Krenz, N. R., & Weaver, L. C. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.740730.x · Cited by 127 · see citing works
The autocrine motility factor receptor gene encodes a novel type of seven transmembrane protein1
Shimizu, K., Tani, M., Watanabe, H., Nagamachi, Y., Niinaka, Y., Shiroishi, T., Ohwada, S., Raz, A., & Yokota, J. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00966-7 · Cited by 119 · see citing works
Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer
Qu, Y., Gharbi, N., Xing, Y., Olsen, J. R., Blicher, P., Dalhus, B., Brokstad, K. A., Lin, B., Oyan, A. M., Zhang, W., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1604520113 · Cited by 117 · see citing works
Dowell, J. A., Johnson, J. A., & Li, L. (2009) · Journal of Proteome Research · doi:10.1021/pr900248y · Cited by 110 · see citing works
Purification of B16-F1 melanoma autocrine motility factor and its receptor.
Silletti, S., Watanabe, H., Hogan, V. A., Nabi, I. R., & Raz, A. (1991) · PubMed · Cited by 108 · see citing works
Yang, Z., Kuboyama, T., & Tohda, C. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00340 · Cited by 91 · see citing works
Self-citationFairbank, M., St-Pierre, P., & Nabi, I. R. (2009) · Molecular BioSystems · doi:10.1039/b820820b · Cited by 88 · see citing works
Marek, R. A., Caruso, M. L., Rostami, A. M., Grinspan, J. B., & Sarma, J. D. (2008) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2008.08.016 · Cited by 83 · see citing works
Tsai, M.-C., Shen, L., Kuo, H., Cheng, H., & Chak, K. (2008) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m800076-mcp200 · Cited by 77 · see citing works
Astroglial-Derived Periostin Promotes Axonal Regeneration after Spinal Cord Injury
Shih, C., Lacagnina, M., Leuer-Bisciotti, K., & Pröschel, C. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.2947-13.2014 · Cited by 70 · see citing works
Extracellular vimentin interacts with insulin-like growth factor 1 receptor to promote axonal growth
Shigyo, M., Kuboyama, T., Sawai, Y., Tada-Umezaki, M., & Tohda, C. (2015) · Scientific Reports · doi:10.1038/srep12055 · Cited by 65 · see citing works
Self-citationTeshigawara, K., Kuboyama, T., Shigyo, M., Nagata, A., Sugimoto, K., Matsuya, Y., & Tohda, C. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.02211.x · Cited by 58 · see citing works
Self-citationShigyo, M., & Tohda, C. (2016) · Scientific Reports · doi:10.1038/srep28293 · Cited by 48 · see citing works
Self-citationAutocrine Motility Factor Promotes HER2 Cleavage and Signaling in Breast Cancer Cells
Kho, D. H., Nangia‐Makker, P., Balan, V., Hogan, V. A., Tait, L. R., Wang, Y., & Raz, A. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-2149 · Cited by 40 · see citing works
Peptide-binding GRP78 protects neurons from hypoxia-induced apoptosis
Goldenberg‐Cohen, N., Raiter, A., Gaydar, V., Dratviman‐Storobinsky, O., Goldstein, T., Weizman, A., & Hardy, B. (2011) · APOPTOSIS · doi:10.1007/s10495-011-0678-x · Cited by 38 · see citing works
Tanabe, N., Kuboyama, T., & Tohda, C. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00446 · Cited by 31 · see citing works
Self-citationShigyo, M., Tanabe, N., Kuboyama, T., Choi, S., & Tohda, C. (2014) · BMC Research Notes · doi:10.1186/1756-0500-7-332 · Cited by 27 · see citing works
Self-citationShima, N., Stolz, D. B., Miyazaki, M., Gohda, E., Higashio, K., & Michalopoulos, G. K. (1998) · Journal of Cellular Physiology · doi:10.1002/(sici)1097-4652(199810)177:1 · Cited by 26 · see citing works
Haga, A., Funasaka, T., Deyashiki, Y., & Raz, A. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.05.005 · Cited by 16 · see citing works
Tian, K., Zhong, W., Zheng, X., Zhang, J., Liu, P., Zhang, W., & Liu, H. (2015) · Scientific Reports · doi:10.1038/srep15101 · Cited by 15 · see citing works
Deng, L., Shi, B., Zhuang, Y., Chu, J., Shi, X., Zhang, S., & Guo, M. (2014) · Cell Transplantation · doi:10.3727/096368913x663578 · Cited by 14 · see citing works
Haga, A., Tanaka, N., Funasaka, T., Hashimoto, K., Nakamura, K., Watanabe, H., Raz, A., & Nagase, H. (2006) · Journal of Molecular Biology · doi:10.1016/j.jmb.2006.02.046 · Cited by 14 · see citing works
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Li, H., Wang, C., He, T., Zhao, T., Chen, Y., Shen, Y., Zhang, X., & Wang, L. (2019) · Theranostics · doi:10.7150/thno.29400 · Cited by 299 · see citing works
Ren, Y., Li, H., Piao, X., Yang, Z., Wang, S., & Ge, Y. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114798 · Cited by 203 · see citing works
Santaella, A., Kuiperij, H. B., van Rumund, A., Esselink, R. A. J., van Gool, A. J., Bloem, B. R., & Verbeek, M. M. (2020) · npj Parkinson s Disease · doi:10.1038/s41531-020-00124-z · Cited by 35 · see citing works
Guo, Y., Wu, J., Wang, M., Wang, X., Jian, Y., Yang, C., & Guo, W. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.1459-21.2022 · Cited by 32 · see citing works
De Kort, A. M., Kuiperij, H. B., Alcolea, D., Kersten, I., Versleijen, A. A. M., Greenberg, S. M., Stoops, E., Schreuder, F. H. B. M., Klijn, C. J. M., Lleó, A., et al. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-021-00899-0 · Cited by 13 · see citing works
Kikuchi, T., Tohda, C., & Suyama, M. (2020) · Scientific Reports · doi:10.1038/s41598-020-76629-7 · Cited by 8 · see citing works
Self-citationZhu, M., Qi, D., Chen, D., Ye, W., Wang, X., Wang, C., Zhou, W. H., Zhou, B., Li, J., & Zhang, K. (2024) · Current Drug Targets · doi:10.2174/0113894501297697240805103744 · Cited by 5 · see citing works
Fodor, R., Voiţă-Mekereş, F., Indrieș, M., Beiușanu, C., Andreescu, G., Voiţă, I. B., Noor, H., & Maghiar, T. A. (2023) · Pharmacophore · doi:10.51847/iae3qqag4f · Cited by 2 · see citing works
Tanie, Y., Kuboyama, T., & Tohda, C. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00789 · Cited by 2 · see citing works
Self-citationSeverity of the neurological deficit of high spinal cord lesions assessed according to etiology
Fodor, R., Davidescu, L., Voiţă-Mekereş, F., Cheregi, C. D., Szilagyi, G., Vîlceanu, I., Davidescu, D., & Manole, F. (2024) · Balneo and PRM Research Journal · doi:10.12680/balneo.2024.724 · Cited by 1 · see citing works
Engert, J., Doll, J., Vona, B., Kasemo, T. E., Spahn, B., Hagen, R., ten Rak, K., & Voelker, J. (2023) · Life · doi:10.3390/life13091858
- Authors
- Tanie, Y., Tanabe, N., Kuboyama, T., & Tohda, C.
- Affiliations
- University of Toyama (JP)
- Corresponding author
- Tohda, Chihiro
- Venue
- Frontiers in Pharmacology
- Publisher
- Frontiers Media SA
- Published
- 2018-10-30
- Volume
- 9
- Pages
- 1228-1228
- ISSN
- 1663-9812 (ISSN-L)
- PMC
- PMC6232869
- OpenAlex
- W2899481557
- Cited by
- 11
- References
- 44
- Citations by year
- 2024: 2 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 1
- FWCI
- 0.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Frontiers in Pharmacology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Institute of Natural Medicine, University of Toyama
- Biosignal Research Center, Kobe University
- Japan Society for the Promotion of Science (26670044, 17H03558, 281002)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- neuroleukin, astrocytes, axon growth, GRP78, spinal cord injury, neuroprotection, cortical neurons, hindlimb motor function
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