CNS-Derived Interleukin-4 Is Essential for the Regulation of Autoimmune Inflammation and Induces a State of Alternative Activation in Microglial Cells
Abstract
Regulation of inflammation in the CNS is essential to prevent irreversible cellular damage that can occur in neurodegenerative diseases such as multiple sclerosis (MS). We investigated the role of interleukin-4 (IL-4) in regulating CNS inflammation using the animal model of MS, experimental autoimmune encephalomyelitis (EAE). We found that CNS-derived IL-4 was a critical regulator because mice with a deficiency in IL-4 production in the CNS, but not the periphery, had exacerbated EAE associated with a significant increase in the absolute number of infiltrating inflammatory cells. We also found that CNS-resident microglial cells in both the resting and activated state produced the protein Ym1, which is a marker of alternatively activated macrophages (aaMΦs), in an IL-4-dependent manner. This aaMΦ phenotype extended to the lack of nitric oxide (NO) production by activated microglial cells, which is a marker of classically activated macrophages. We also show that IL-4 induced the expression of Ym1 in peripheral infiltrating macrophages, which also produce NO. Thus, macrophages that migrate into the CNS exhibit a dual phenotype. These data indicate that IL-4 production in the CNS is essential for controlling autoimmune inflammation by inducing a microglial cell aaMΦ phenotype. Macrophages that have undergone alternative activation have been shown to be important in tissue repair; thus, our results suggest a new role for microglial cells in the regulation of inflammation in the CNS.
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Quiescent microglia show properties of M2 macrophages and M2 macrophages are crucial for suppression of EAE.
“These results are consistent with our observations that quiescent microglia show properties of M2 macrophages and that M2 macrophages are crucial for the suppression of EAE45.”
From MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α–PU.1 pathway (2011) · cites this paper as [45]
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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
Biochemical and functional characterization of three activated macrophage populations
Edwards, J. P., Zhang, X., Frauwirth, K. A., & Mosser, D. M. (2006) · Journal of Leukocyte Biology · doi:10.1189/jlb.0406249 · Cited by 863 · see citing works
Butovsky, O. (2006) · Journal of Clinical Investigation · doi:10.1172/jci26836 · Cited by 261 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases
Tang, Y., & Le, W. (2016) · Molecular Neurobiology · doi:10.1007/s12035-014-9070-5 · Cited by 2,190 · see citing works
Kigerl, K. A., Gensel, J. C., Ankeny, D. P., Alexander, J. K., Donnelly, D. J., & Popovich, P. G. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3257-09.2009 · Cited by 2,130 · see citing works
Microglial <scp>M1/M2</scp> polarization and metabolic states
Orihuela, R., McPherson, C. A., & Harry, G. J. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13139 · Cited by 2,070 · see citing works
Neuroinflammation and M2 Microglia: The Good, the Bad, and the Inflamed
Cherry, J. D., Olschowka, J. A., & O’Banion, M. K. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-98 · Cited by 1,748 · see citing works
Ponomarev, E. D., Veremeyko, T., Barteneva, N., Krichevsky, A. M., & Weiner, H. L. (2011) · Nature Medicine · doi:10.1038/nm.2266 · Cited by 787 · see citing works
Self-citationMicroglia and neurodegeneration: The role of systemic inflammation
Cunningham, C. (2013) · Glia · doi:10.1002/glia.22350 · Cited by 769 · see citing works
Minocycline selectively inhibits M1 polarization of microglia
Kobayashi, K., Imagama, S., Ohgomori, T., Hirano, K., Uchimura, K., Sakamoto, K., Hirakawa, A., Takeuchi, H., Suzumura, A., Ishiguro, N., et al. (2013) · Cell Death & Disease · doi:10.1038/cddis.2013.54 · Cited by 742 · see citing works
IL-4 in the brain: a cytokine to remember
Gadani, S. P., Cronk, J. C., Norris, G. T., & Kipnis, J. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1202246 · Cited by 549 · see citing works
Microglia in Central Nervous System Inflammation and Multiple Sclerosis Pathology
Voet, S., Prinz, M., & van Loo, G. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.11.005 · Cited by 503 · see citing works
Michelucci, A., Heurtaux, T., Grandbarbe, L., Morga, E., & Heuschling, P. (2009) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2009.02.003 · Cited by 411 · see citing works
Jimenez, S., Baglietto-Vargas, D., Caballero, C., Moreno-Gonzalez, I., Torres, M., Sanchez-Varo, R., Ruano, D., Vizuete, M., Gutierrez, A., & Vitorica, J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3024-08.2008 · Cited by 383 · see citing works
“Multiple in vitro reports have probed the influence of IL-4 in the development of a non-proinflammatory alternative phenotype (Iribarren et al., 2005; Butovsky et al., 2005; Ponomarev et al., 2007; Lyons et al., 2007a,b).”
BackgroundAlternative activation of macrophages: immune function and cellular biology
Varin, A., & Gordon, S. (2009) · Immunobiology · doi:10.1016/j.imbio.2008.11.009 · Cited by 361 · see citing works
Microglia in ALS: The Good, The Bad, and The Resting
Henkel, J. S., Beers, D. R., Zhao, W., & Appel, S. H. (2009) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-009-9171-5 · Cited by 353 · see citing works
Depletion of microglia exacerbates postischemic inflammation and brain injury
Jin, W.-N., Shi, S. X.-Y., Li, Z., Li, M., Wood, K., Gonzales, R. J., & Liu, Q. (2017) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x17694185 · Cited by 351 · see citing works
“On the other hand, microglia also have an anti-inflammatory role by producing factors such as IL-4 and IL-10 during the resolution phase of brain inflammation, upon their return back to a surveillance state.(13,14) These properties support microglia”
Alternatively activated macrophages in infection and autoimmunity
Fairweather, D., & Cihakova, D. (2009) · Journal of Autoimmunity · doi:10.1016/j.jaut.2009.09.012 · Cited by 290 · see citing works
Kumar, A., Stoica, B. A., Sabirzhanov, B., Burns, M. P., Faden, A. I., & Loane, D. J. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.11.013 · Cited by 244 · see citing works
Microglia affect α-synuclein cell-to-cell transfer in a mouse model of Parkinson’s disease
George, S., Rey, N. L., Tyson, T., Esquibel, C., Meyerdirk, L., Schulz, E., Pierce, S., Burmeister, A. R., Madaj, Z., Steiner, J. A., et al. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0335-3 · Cited by 229 · see citing works
Retinal microglia initiate neuroinflammation in ocular autoimmunity
Okunuki, Y., Mukai, R., Nakao, T., Tabor, S. J., Butovsky, O., Dana, R., Ksander, B. R., & Connor, K. M. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1820387116 · Cited by 216 · see citing works
Modulating neurotoxicity through CX3CL1/CX3CR1 signaling
Limatola, C., & Ransohoff, R. M. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00229 · Cited by 210 · see citing works
Functional diversity of microglia – how heterogeneous are they to begin with?
Hanisch, U.-K. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00065 · Cited by 195 · see citing works
Speisman, R. B., Kumar, A., Rani, A., Foster, T. C., & Ormerod, B. K. (2013) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2012.09.013 · Cited by 187 · see citing works
Hypothalamic innate immune reaction in obesity
Kälin, S., Heppner, F. L., Bechmann, I., Prinz, M., Tschöp, M. H., & Yi, C.-X. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.48 · Cited by 167 · see citing works
TGFβ signalling plays an important role in IL4-induced alternative activation of microglia
Zhou, X., Spittau, B., & Krieglstein, K. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-210 · Cited by 159 · see citing works
Microglial activation in the pathogenesis of Huntington's disease
Yang, H.-M., Yang, S., Huang, S.-S., Tang, B.-S., & Guo, J.-F. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00193 · Cited by 151 · see citing works
Arginase 1+ microglia reduce Aβ plaque deposition during IL-1β-dependent neuroinflammation
Cherry, J. D., Olschowka, J. A., & O’Banion, M. K. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0411-8 · Cited by 152 · see citing works
Vereyken, E. J., Heijnen, P. D., Baron, W., de Vries, E. H., Dijkstra, C. D., & Teunissen, C. E. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-58 · Cited by 108 · see citing works
“51. van Zwam M, Huizinga R, Melief MJ, Wierenga-Wolf AF, van Meurs M, Voerman JS, Biber KP, Boddeke HW, Hopken UE, Meisel C, Meisel A, Bechmann I, Hintzen RQ, ’t Hart BA, Amor S, Laman JD, Boven LA: Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE.”
BackgroundInfluentialCordaro, M., Cuzzocrea, S., & Crupi, R. (2020) · Antioxidants · doi:10.3390/antiox9030216 · Cited by 98 · see citing works
Kiyota, T., Machhi, J., Lu, Y., Dyavarshetty, B., Nemati, M., Yokoyama, I., Mosley, R. L., & Gendelman, H. E. (2018) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2018.03.009 · Cited by 80 · see citing works
Rossi, C., Cusimano, M., Zambito, M., Finardi, A., Capotondo, A., Garcia-Manteiga, J. M., Comi, G., Furlan, R., Martino, G., & Muzio, L. (2018) · Cell Death & Disease · doi:10.1038/s41419-018-0288-4 · Cited by 77 · see citing works
Guglielmetti, C., Le Blon, D., Santermans, E., Salas-Perdomo, A., Daans, J., De Vocht, N., Shah, D., Hoornaert, C., Praet, J., Peerlings, J., et al. (2016) · Glia · doi:10.1002/glia.23053 · Cited by 76 · see citing works
Dynamic Responses of Microglia in Animal Models of Multiple Sclerosis
Plastini, M. J., Desu, H. L., & Brambilla, R. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00269 · Cited by 48 · see citing works
Interleukin-4 Is a Participant in the Regulation of Depressive-like Behavior
Wachholz, S., Knorr, A., Mengert, L., Plümper, J., Sommer, R., Juckel, G., & Friebe, A. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.03.020 · Cited by 45 · see citing works
Li, L., Ni, L., Heary, R. F., & Elkabes, S. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01748-x · Cited by 34 · see citing works
- Authors
- Ponomarev, E. D., Maresz, K., Tan, Y., & Dittel, B. N.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-10-03
- Volume
- 27
- Issue
- 40
- Pages
- 10714-10721
- ISSN
- 0270-6474
- 1529-2401
- Cited by
- 339
- References
- 3
- Language
- en
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