TGF-β and LPS modulate ADP-induced migration of microglial cells through P2Y1 and P2Y12 receptor expression
Abstract
Nucleotides act as early signals for microglial recruitment to sites of CNS injury. As microglial motility and activation can be influenced by several local factors at the site of the lesion, we investigated the effects of interferon-gamma, lipopolysaccharide (LPS) or transforming growth factor-β (TGF-β) addition to mixed glial cell cultures, on microglial migration in response to ADP, P2Y12 and P2Y1 mRNA expression as well as on the expression of an array of genes associated with the process of microglial activation. First, we demonstrated, by pharmacological inhibition and by using small interfering RNAs, that in addition to P2Y12, P2Y1 is involved in ADP-stimulated microglial migration. The ability of specific agonists to induce Ca(2+) mobilization further confirmed the expression of functional P2Y receptors in microglia. Then, we found that migratory capability and expression of both P2Y receptors were abrogated in microglial cells from LPS-stimulated mixed glial cultures, while TGF-β increased ADP-induced migration and the expression of P2Y12 and P2Y1 receptors. Interferon-gamma did not influence receptor expression or microglial migration. Finally, the patterns of gene expression induced in microglia by LPS or TGF-β treatment of mixed glial cultures were clearly distinct. LPS induced a set of classical pro-inflammatory genes, whereas TGF-β increased the expression of genes associated with atypical microglial phenotype, namely arginase-1 and TGF-β genes. These results imply that both P2Y1 and P2Y12 may guide microglia toward the lesion. They also suggest that the modulation of microglial purinergic receptors expression by local factors, through direct and/or astrocyte-mediated actions, may represent a novel mechanism affecting neuroinflammatory response.
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iMGLs express the microglial-enriched purinergic receptor P2ry12.
“iMGLs express the microglial-enriched purinergic receptor P2ry12, which sense extracellular nucleotides from degenerating neurons, and is critical for microglial homeostatic function (De Simone et al., 2010; Moore et al., 2015) (Figure S2A,B).”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as De Simone et al., 2010
Cites
Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005) · Science · doi:10.1126/science.1110647 · Cited by 5,827 · see citing works
Monocyte and macrophage heterogeneity
Gordon, S., & Taylor, P. R. (2005) · Nature Reviews Immunology · doi:10.1038/nri1733 · Cited by 5,190 · see citing works
Alternative activation of macrophages: mechanism and functions
Gordon, S., & Martinez, F. O. (2010) · Immunity · doi:10.1016/j.immuni.2010.05.007 · Cited by 4,197 · see citing works
ATP mediates rapid microglial response to local brain injury in vivo
Davalos, D., Grutzendler, J., Yang, G., Kim, J. V., Zuo, Y., Jung, S., Littman, D. R., Dustin, M. L., & Gan, W.-B. (2005) · Nature Neuroscience · doi:10.1038/nn1472 · Cited by 3,913 · see citing works
Microglia: Active sensor and versatile effector cells in the normal and pathologic brain
Hanisch, U.-K., & Kettenmann, H. (2007) · Nature Neuroscience · doi:10.1038/nn1997 · Cited by 3,676 · see citing works
TRANSFORMING GROWTH FACTOR-β REGULATION OF IMMUNE RESPONSES
Li, M. O., Wan, Y. Y., Sanjabi, S., Robertson, A.-K. L., & Flavell, R. A. (2005) · Annual Review of Immunology · doi:10.1146/annurev.immunol.24.021605.090737 · Cited by 2,199 · see citing works
Microglial physiology: unique stimuli, specialized responses
Ransohoff, R. M., & Perry, V. H. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132528 · Cited by 1,858 · see citing works
The P2Y12 receptor regulates microglial activation by extracellular nucleotides
Haynes, S. E., Hollopeter, G., Yang, G., Kurpius, D., Dailey, M. E., Gan, W.-B., & Julius, D. (2006) · Nature Neuroscience · doi:10.1038/nn1805 · Cited by 1,542 · see citing works
Systemic infections and inflammation affect chronic neurodegeneration
Perry, V. H., Cunningham, C., & Holmes, C. (2007) · Nature Reviews Immunology · doi:10.1038/nri2015 · Cited by 1,027 · see citing works
Heterogeneity of Microglial Activation in the Innate Immune Response in the Brain
Colton, C. A. (2009) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-009-9164-4 · Cited by 871 · see citing works
Purinergic signalling in the nervous system: an overview
Abbracchio, M. P., Burnstock, G., Verkhratsky, A., & Zimmermann, H. (2008) · Trends in Neurosciences · doi:10.1016/j.tins.2008.10.001 · Cited by 856 · see citing works
Regulation of innate immune responses in the brain
Rivest, S. (2009) · Nature Reviews Immunology · doi:10.1038/nri2565 · Cited by 843 · see citing works
UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis
Koizumi, S., Shigemoto-Mogami, Y., Nasu-Tada, K., Shinozaki, Y., Ohsawa, K., Tsuda, M., Joshi, B. V., Jacobson, K. A., Kohsaka, S., & Inoue, K. (2007) · Nature · doi:10.1038/nature05704 · Cited by 802 · see citing works
Nonpsychotropic Cannabinoid Receptors Regulate Microglial Cell Migration
Walter, L. M., Franklin, A. A., Witting, A., Wade, C. B., Xie, Y., Kunos, G., Mackie, K., & Stella, N. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-04-01398.2003 · Cited by 666 · see citing works
Purinergic signalling and disorders of the central nervous system
Burnstock, G. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2605 · Cited by 640 · see citing works
Lehnardt, S. (2009) · Glia · doi:10.1002/glia.20928 · Cited by 596 · see citing works
Central role of the P2Y12 receptor in platelet activation
Dorsam, R. T., & Kunapuli, S. P. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20986 · Cited by 584 · see citing works
Honda, S., Sasaki, Y., Ohsawa, K., Imai, Y., Nakamura, Y., Inoue, K., & Kohsaka, S. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-06-01975.2001 · Cited by 561 · see citing works
Microglia Biology in Health and Disease
Garden, G. A., & Möller, T. (2006) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-006-9015-5 · Cited by 494 · see citing works
Microglial phenotype: is the commitment reversible?
Schwartz, M., Butovsky, O., Brück, W., & Hanisch, U.-K. (2006) · Trends in Neurosciences · doi:10.1016/j.tins.2005.12.005 · Cited by 434 · see citing works
Adenosine A2A receptor mediates microglial process retraction
Orr, A. G., Orr, A. L., Traynelis, S. F., Gross, R. E., & Traynelis, S. F. (2009) · Nature Neuroscience · doi:10.1038/nn.2341 · Cited by 361 · see citing works
Involvement of P2X 4 and P2Y 12 receptors in ATP‐induced microglial chemotaxis
Ohsawa, K., Irino, Y., Nakamura, Y., Akazawa, C., Inoue, K., & Kohsaka, S. (2007) · Glia · doi:10.1002/glia.20489 · Cited by 301 · see citing works
Purinergic signalling in inflammation of the central nervous system
Virgilio, F. D., Ceruti, S., Bramanti, P., & Abbracchio, M. P. (2009) · Trends in Neurosciences · doi:10.1016/j.tins.2008.11.003 · Cited by 210 · see citing works
Boucsein, C., Zacharias, R., Färber, K., Pavlovic, S., Hanisch, U., & Kettenmann, H. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02663.x · Cited by 203 · see citing works
Advances in signalling by extracellular nucleotides
Communi, D., Janssens, R., Suarez-Huerta, N., Robaye, B., & Boeynaems, J. (2000) · Cellular Signalling · doi:10.1016/s0898-6568(00)00083-8 · Cited by 187 · see citing works
P2Y12receptor‐mediated integrin‐β1 activation regulates microglial process extension induced by ATP
Ohsawa, K., Irino, Y., Sanagi, T., Nakamura, Y., Suzuki, E., Inoue, K., & Kohsaka, S. (2010) · Glia · doi:10.1002/glia.20963 · Cited by 157 · see citing works
Metabotropic P2 receptor activation regulates oligodendrocyte progenitor migration and development
Agresti, C., Meomartini, M. E., Amadio, S., Ambrosini, E., Serafini, B., Franchini, L., Volonté, C., Aloisi, F., & Visentin, S. (2005) · Glia · doi:10.1002/glia.20160 · Cited by 153 · see citing works
Self-citationLevi, G., Patrizio, M., Bernardo, A., Petrucci, T. C., & Agresti, C. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.4.1541 · Cited by 148 · see citing works
Diverse microglial motility behaviors during clearance of dead cells in hippocampal slices
Petersen, M. A., & Dailey, M. E. (2004) · Glia · doi:10.1002/glia.10362 · Cited by 139 · see citing works
de Jong, E. K., Dijkstra, I. M., Hensens, M., Brouwer, N., van Amerongen, M. J., Liem, R. S. B., Boddeke, H. W. G. M., & Biber, K. P. H. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.1019-05.2005 · Cited by 136 · see citing works
Purinergic systems in microglia
Inoue, K. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8210-3 · Cited by 132 · see citing works
Ifuku, M., Färber, K., Okuno, Y., Yamakawa, Y., Miyamoto, T., Nolte, C., Merrino, V., Kita, S., Iwamoto, T., Komuro, I., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.3467-07.2007 · Cited by 131 · see citing works
Li, Q., Wei, S., Zhang, D., Hu, X., Xu, Z., Wilson, B. C., Benna, J. E., Hong, J., & Flood, P. M. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.1.660 · Cited by 128 · see citing works
Glutamate induces directed chemotaxis of microglia
Liu, G. J., Nagarajah, R., Banati, R. B., & Bennett, M. R. (2009) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2009.06659.x · Cited by 115 · see citing works
Akt activation is involved in P2Y12 receptor‐mediated chemotaxis of microglia
Irino, Y., Nakamura, Y., Inoue, K., Kohsaka, S., & Ohsawa, K. (2008) · Journal of Neuroscience Research · doi:10.1002/jnr.21610 · Cited by 110 · see citing works
Schilling, T., Nitsch, R., Heinemann, U., Haas, D., & Eder, C. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01661.x · Cited by 108 · see citing works
Morphine-Induced Chemotaxis and Brain-Derived Neurotrophic Factor Expression in Microglia
Takayama, N., & Ueda, H. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.3170-04.2005 · Cited by 97 · see citing works
Simone, R. D., Ajmone‐Cat, M. A., & Minghetti, L. (2004) · Molecular Neurobiology · doi:10.1385/mn:29:2:197 · Cited by 88 · see citing works
Self-citationHerrera‐Molina, R., & Rommy von Bernhardi, M. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.01.003 · Cited by 74 · see citing works
Simone, R. D., Ajmone‐Cat, M. A., Tirassa, P., & Minghetti, L. (2003) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/62.2.208 · Cited by 72 · see citing works
Self-citationSimone, R. D., Ambrosini, E., Carnevale, D., Ajmone‐Cat, M. A., & Minghetti, L. (2007) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2007.07.020 · Cited by 63 · see citing works
Self-citationPotucek, Y., Crain, J. M., & Watters, J. J. (2006) · Neurochemistry International · doi:10.1016/j.neuint.2006.04.005 · Cited by 61 · see citing works
Visentin, S., Nuccio, C. D., & Bellenchi, G. C. (2006) · Purinergic Signalling · doi:10.1007/s11302-006-9023-1 · Cited by 22 · see citing works
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iPSC-derived human microglia-like cells to study neurological diseases
Abud, E. M., Ramirez, R. N., Martinez, E. S., Healy, L. M., Nguyen, C. H. H., Newman, S. A., Yeromin, A. V., Scarfone, V. M., Marsh, S. E., Fimbres, C., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.03.042 · Cited by 1,154 · see citing works
P2Y12 expression and function in alternatively activated human microglia
Moore, C. S., Ase, A. R., Kinsara, A., Rao, V. T. S., Michell-Robinson, M., Leong, S. Y., Butovsky, O., Ludwin, S. K., Séguéla, P., Bar-Or, A., et al. (2015) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000000080 · Cited by 212 · see citing works
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Franco-Bocanegra, D. K., McAuley, C., Nicoll, J. A. R., & Boche, D. (2019) · Cells · doi:10.3390/cells8060639 · Cited by 147 · see citing works
Zhang, Z., Bassam, B., Thomas, A. G., Williams, M., Liu, J., Nance, E., Rojas, C., Slusher, B. S., & Kannan, S. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.06.010 · Cited by 84 · see citing works
- Authors
- De Simone, R., Niturad, C. E., De Nuccio, C., Ajmone‐Cat, M. A., Visentin, S., & Minghetti, L.
- Affiliations
- Istituto Superiore di Sanità (IT)
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2010-07-30
- Volume
- 115
- Issue
- 2
- Pages
- 450-459
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2132141205
- Cited by
- 104
- References
- 43
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 9 · 2023: 7 · 2022: 5 · 2021: 8 · 2020: 9 · 2019: 8 · 2018: 7 · 2017: 4 · 2016: 7 · 2015: 4 · 2014: 10 · 2013: 7 · 2012: 5
- FWCI
- 3.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- microglial migration, P2Y1 receptor, P2Y12 receptor, ADP, lipopolysaccharide, TGF-beta, interferon-gamma, purinergic receptors, microglial activation, neuroinflammation, arginase-1, calcium mobilization, mixed glial cultures
- MeSH terms
- Adenosine Diphosphate, Animals, Animals, Newborn, Calcium, Cell Movement, Cells, Cultured, Cerebral Cortex, Gene Expression Regulation, Interferon-gamma, Lipopolysaccharides, Thionucleotides, Transforming Growth Factor beta, Microglia, Receptors, Purinergic P2, RNA, Small Interfering, Rats, Receptors, Purinergic P2Y1, Receptors, Purinergic P2Y12
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