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IL-4 Signaling Drives a Unique Arginase+/IL-1 + Microglia Phenotype and Recruits Macrophages to the Inflammatory CNS: Consequences of Age-Related Deficits in IL-4R after Traumatic Spinal Cord Injury
Open accessAbstract
Alternative activation of microglia/macrophages (M2a) by interleukin (IL)-4 is purported to support intrinsic growth and repair processes after CNS injury. Nonetheless, alternative activation of microglia is poorly understood in vivo, particularly in the context of inflammation, injury, and aging. Here, we show that aged mice (18-19 months) had reduced functional recovery after spinal cord injury (SCI) associated with impaired induction of IL-4 receptor α (IL-4Rα) on microglia. The failure to successfully promote an IL-4/IL-4Rα response in aged mice resulted in attenuated arginase (M2a associated), IL-1β, and chemokine ligand 2 (CCL2) expression, and diminished recruitment of IL-4Rα(+) macrophages to the injured spinal cord. Furthermore, the link between reduced IL-4Rα expression and reduced arginase, IL-1β, and CCL2 expression was confirmed using adult IL-4Rα knock-out (IL-4Rα(KO)) mice. To better understand IL-4Rα-mediated regulation of active microglia, a series of studies was completed in mice that were peripherally injected with lipopolysaccharide and later provided IL-4 by intracerebroventricular infusion. These immune-based studies demonstrate that inflammatory-induced IL-4Rα upregulation on microglia was required for the induction of arginase by IL-4. In addition, IL-4-mediated reprogramming of active microglia enhanced neurite growth ex vivo and increased inflammatory gene expression (i.e., IL-1β and CCL2) and the corresponding recruitment of CCR2(+)/IL-4Rα(+)/arginase(+) myeloid cells in vivo. IL-4 reprogrammed active microglia to a unique and previously unreported phenotype (arginase(+)/IL-1β(+)) that augmented neurite growth and enhanced recruitment of peripheral IL-4Rα(+) myeloid cells to the CNS. Moreover, this key signaling cascade was impaired with age corresponding with reduced functional recovery after SCI.
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“For example, compared with adult mice, the aged mice showed deficient IL-4Rα expression, that corresponded with reduced arginase production and impaired functional recovery following spinal cord injury (Fenn et al, 2014).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Fenn et al, 2014
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Exploring the full spectrum of macrophage activation
Mosser, D. M., & Edwards, J. P. (2008) · Nature Reviews Immunology · doi:10.1038/nri2448 · Cited by 9,144
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
Self-citationBasso, 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
Self-citationRepertoire of microglial and macrophage responses after spinal cord injury
David, S., & Kroner, A. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3053 · Cited by 1,297
Butovsky, O., Ziv, Y., Schwartz, A., Landa, G., Talpalar, A. E., Pluchino, S., Martino, G., & Schwartz, M. (2006) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2005.10.006 · Cited by 923
Arginase-1–Expressing Macrophages Suppress Th2 Cytokine–Driven Inflammation and Fibrosis
Pesce, J. T., Ramalingam, T. R., Mentink-Kane, M. M., Wilson, M. S., El Kasmi, K. C., Smith, A. M., Thompson, R. W., Cheever, A. W., Murray, P. J., & Wynn, T. A. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000371 · Cited by 816
Shechter, R., London, A., Varol, C., Raposo, C., Cusimano, M., Yovel, G., Rolls, A., Mack, M., Pluchino, S., Martino, G., et al. (2009) · PLoS Medicine · doi:10.1371/journal.pmed.1000113 · Cited by 770
Microglia derived from aging mice exhibit an altered inflammatory profile
Sierra, A., Gottfried‐Blackmore, A. C., McEwen, B. S., & Bulloch, K. (2007) · Glia · doi:10.1002/glia.20468 · Cited by 688
Shechter, R., Miller, O., Yovel, G., Rosenzweig, N., London, A., Ruckh, J., Kim, K.-W., Klein, E., Kalchenko, V., Bendel, P., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.02.012 · Cited by 683
Wohleb, E. S., Hanke, M. L., Corona, A. W., Powell, N. D., Stiner, L. M., Bailey, M. T., Nelson, R. J., Godbout, J. P., & Sheridan, J. F. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.0450-11.2011 · Cited by 638
Self-citationHenry, C. J., Huang, Y., Wynne, A. M., & Godbout, J. P. (2009) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2008.09.002 · Cited by 565
Self-citationWohleb, E. S., Powell, N. D., Godbout, J. P., & Sheridan, J. F. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.1671-13.2013 · Cited by 563
Self-citationIL-4-Induced Arginase 1 Suppresses Alloreactive T Cells in Tumor-Bearing Mice
Bronte, V., Serafini, P., Santo, C. D., Marigo, I., Tosello, V., Mazzoni, A., Segal, D. M., Staib, C., Löwel, M., Sutter, G., et al. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.1.270 · Cited by 526
Rats and mice exhibit distinct inflammatory reactions after spinal cord injury
Sroga, J. M., Jones, T. B., Kigerl, K. A., McGaughy, V. M., & Popovich, P. G. (2003) · The Journal of Comparative Neurology · doi:10.1002/cne.10736 · Cited by 369
Self-citationTGFβ produced by IL‐10 redirected astrocytes attenuates microglial activation
Norden, D. M., Fenn, A. M., Dugan, A., & Godbout, J. P. (2014) · Glia · doi:10.1002/glia.22647 · Cited by 332
Self-citationKigerl, K. A., Lai, W., Rivest, S., Hart, R. P., Satoskar, A. R., & Popovich, P. G. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04524.x · Cited by 298
Self-citationDurrenberger, P. F., Ettorre, A., Kamel, F. O., Webb, L. V., Sim, M. J. W., Nicholas, R. S., Malik, O., Reynolds, R., Boyton, R. J., & Altmann, D. M. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-1 · Cited by 286
Fenn, A. M., Gensel, J. C., Huang, Y., Popovich, P. G., Lifshitz, J., & Godbout, J. P. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.10.014 · Cited by 283
Self-citationCao, Q., Xu, X., DeVries, W. H., Enzmann, G. U., Ping, P., Tsoulfas, P., Wood, P. M., Bunge, M. B., & Whittemore, S. R. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.1065-05.2005 · Cited by 281
Xu, H., Chen, M., Manivannan, A., Lois, N., & Forrester, J. V. (2008) · Aging Cell · doi:10.1111/j.1474-9726.2007.00351.x · Cited by 277
Wohleb, E. S., Fenn, A. M., Pacenta, A. M., Powell, N. D., Sheridan, J. F., & Godbout, J. P. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.02.003 · Cited by 275
Self-citationKigerl, K. A., McGaughy, V. M., & Popovich, P. G. (2005) · The Journal of Comparative Neurology · doi:10.1002/cne.20827 · Cited by 271
Self-citationKumar, 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
Macrophages Promote Axon Regeneration with Concurrent Neurotoxicity
Gensel, J. C., Nakamura, S., Guan, Z., van Rooijen, N., Ankeny, D. P., & Popovich, P. G. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.3992-08.2009 · Cited by 237
Self-citationHuang, Y., Henry, C. J., Dantzer, R., Johnson, R. W., & Godbout, J. P. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.04.012 · Cited by 226
Self-citationDonnelly, D. J., Longbrake, E. E., Shawler, T. M., Kigerl, K. A., Lai, W., Tovar, C. A., Ransohoff, R. M., & Popovich, P. G. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.2114-11.2011 · Cited by 219
Self-citationTraumatic Spinal Cord Injury Produced by Controlled Contusion in Mouse
Jakeman, L. B., Guan, Z., Wei, P. Y., Ponnappan, R. K., Dzwonczyk, R. R., Popovich, P. G., & Stokes, B. T. (2000) · Journal of Neurotrauma · doi:10.1089/neu.2000.17.299 · Cited by 209
Self-citationGuerrero, A. R., Uchida, K., Nakajima, H., Watanabe, S., Nakamura, M., Johnson, W. E., & Baba, H. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-40 · Cited by 201
Fenn, A. M., Henry, C. J., Huang, Y., Dugan, A., & Godbout, J. P. (2012) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2011.10.003 · Cited by 198
Self-citationKohanbash, G., McKaveney, K., Sakaki, M., Ueda, R., Mintz, A. H., Amankulor, N. A., Fujita, M., Ohlfest, J. R., & Okada, H. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-4124 · Cited by 189
Exacerbated glial response in the aged mouse hippocampus following controlled cortical impact injury
Sandhir, R., Onyszchuk, G., & Berman, N. E. J. (2008) · Experimental Neurology · doi:10.1016/j.expneurol.2008.06.013 · Cited by 183
Kwon, M. J., Kim, J., Shin, H., Jeong, S. R., Kang, Y. M., Choi, J. Y., Hwang, D. H., & Kim, B. G. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.0278-13.2013 · Cited by 177
Zhao, W., Xie, W., Xiao, Q., Beers, D. R., & Appel, S. H. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04172.x · Cited by 176
(2007) · Journal of Spinal Cord Medicine · doi:10.1080/10790268.2007.11753942 · Cited by 141
IL‐4 attenuates the neuroinflammation induced by amyloid‐β in vivo and in vitro
Lyons, A., Griffin, R. J., Costelloe, C., Clarke, R. M., & Lynch, M. A. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04370.x · Cited by 129
Mortality rates in geriatric patients with spinal cord injuries
Fassett, D. R., Harrop, J. S., Maltenfort, M., Jeyamohan, S. B., Ratliff, J. K., Anderson, D. G., Hilibrand, A. S., Albert, T. J., Vaccaro, A. R., & Sharan, A. D. (2007) · Journal of Neurosurgery Spine · doi:10.3171/spi-07/09/277 · Cited by 123
Lee, D. C., Ruiz, C. R., Lebson, L. A., Selenica, M. B., Rizer, J., Hunt, J. B., Rojiani, R., Reid, P., Kammath, S., Nash, K. R., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.12.014 · Cited by 122
Pathogenesis of Twin-Twin Transfusion Syndrome: The Renin-Angiotensin System Hypothesis
Mahieu‐Caputo, D., MULLER, F. M., Joly, D., Gübler, M.-C., Bidois, J. L., Fermont, L., Dumez, Y., & Dommergues, M. (2001) · Fetal Diagnosis and Therapy · doi:10.1159/000053919 · Cited by 121
Onyszchuk, G., He, Y., Berman, N. E. J., & Brooks, W. M. (2008) · Journal of Neurotrauma · doi:10.1089/neu.2007.0430 · Cited by 120
Stirling, D. P., Cummins, K., Mishra, M. K., Teo, W., Yong, V. W., & Stys, P. K. (2013) · Brain · doi:10.1093/brain/awt341 · Cited by 114
Butti, E., Bergami, A., Recchia, A., Brambilla, E., Carro, U. D., Amadio, S., Cattalini, A., Esposito, M., Stornaiuolo, A., Comı, G., et al. (2008) · Gene Therapy · doi:10.1038/gt.2008.10 · Cited by 97
Saiwai, H., Kumamaru, H., Ohkawa, Y., Kubota, K., Kobayakawa, K., Yamada, H., Yokomizo, T., Iwamoto, Y., & Okada, S. (2012) · Journal of Neurochemistry · doi:10.1111/jnc.12135 · Cited by 96
Barrette, B., Calvo, E. L., Vallières, N., & Lacroix, S. (2010) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2010.07.249 · Cited by 96
Interleukin-4-inhibited mRNA expression in mixed rat glial and in isolated microglial cultures
Kitamura, Y., Taniguchi, T., Kimura, H., Nomura, Y., & Gebicke‐Haerter, P. J. (2000) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(00)00239-3 · Cited by 68
Lee, S. I., Jeong, S. R., Kang, Y. M., Han, D. H., Jin, B. K., Namgung, U., & Kim, B. G. (2010) · Journal of Neuroscience Research · doi:10.1002/jnr.22411 · Cited by 50
A Nationwide Epidemiological Study of Spinal Cord Injury in Geriatric Patients in Taiwan
Chen, H.-Y., Chen, S.-S., Chiu, W.-T., Lee, L.-S., Hung, C.-I., Hung, C.-L., Wang, Y.-C., Hung, C.-C., Lin, L.-S., Shih, Y., et al. (1997) · Neuroepidemiology · doi:10.1159/000109693 · Cited by 46
Puntambekar, S. S., Davis, D. S., Hawel, L., Crane, J., Byus, C. V., & Carson, M. J. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2010.12.016 · Cited by 40
Voluntary running attenuates age-related deficits following SCI
Siegenthaler, M. M., Berchtold, N. C., Cotman, C. W., & Keirstead, H. S. (2007) · Experimental Neurology · doi:10.1016/j.expneurol.2007.10.019 · Cited by 39
Gwak, Y. S., Hains, B. C., Johnson, K. M., & Hulsebosch, C. E. (2004) · Neuroscience Letters · doi:10.1016/j.neulet.2004.03.019 · Cited by 28
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Metadata
- Authors
- Fenn, A. M., Hall, J. C. E., Gensel, J. C., Popovich, P. G., & Godbout, J. P.
- Affiliations
- The Ohio State University (US)
- University of Kentucky (US)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-06-25
- Volume
- 34
- Issue
- 26
- Pages
- 8904-8917
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4069360
- OpenAlex
- W2065700461
- Cited by
- 207
- References
- 50
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 12 · 2023: 16 · 2022: 21 · 2021: 14 · 2020: 22 · 2019: 12 · 2018: 16 · 2017: 19 · 2016: 31 · 2015: 15 · 2014: 5
- FWCI
- 12.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UKnowledge (University of Kentucky) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Ohio State University
- National Institute on Aging (R01AG033028)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Spinal Cord Injury Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- IL-4 signaling, IL-4 receptor alpha, microglia, macrophage recruitment, arginase, IL-1β, MCP-1, spinal cord injury, aging, functional recovery, neurite outgrowth, CCR2, lipopolysaccharide, myeloid cell recruitment, neuroinflammation
- MeSH terms
- Aging, Animals, Arginase, Disease Models, Animal, Inflammation, Macrophage Activation, Macrophages, Spinal Cord Injuries, Signal Transduction, Interleukin-4, Neurites, Microglia, Chemokine CCL2, Receptors, Interleukin-4, Mice, Interleukin-1beta
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