The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.
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.
Overview
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
Verification
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?
In the citing paper
“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
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
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-citation
Cited by
Sorted by citations
Microglial brain region-dependent diversity and selective regional sensitivities to aging
Grabert, K., Michoel, T., Karavolos, M. H., Clohisey, S., Baillie, J. K., Stevens, M. P., Freeman, T. C., Summers, K. M., & McColl, B. W. (2016) · Nature Neuroscience · doi:10.1038/nn.4222 · Cited by 1,151
Microglia in the TBI brain: The good, the bad, and the dysregulated
Loane, D. J., & Kumar, A. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2015.08.018 · Cited by 846
Tissue macrophages: heterogeneity and functions
Gordon, S., & Plüddemann, A. (2017) · BMC Biology · doi:10.1186/s12915-017-0392-4 · Cited by 628
Norden, D. M., Trojanowski, P. J., Villanueva, E., Navarro, E., & Godbout, J. P. (2015) · Glia · doi:10.1002/glia.22930 · Cited by 623
Self-citationMicroglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy
Muzio, L., Viotti, A., & Martino, G. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.742065 · Cited by 581
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
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
