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

Fenn, A. M.; Hall, J. C. E.; Gensel, J. C.; Popovich, P. G.; Godbout, J. P.

doi:10.1523/jneurosci.1146-14.2014

Cited by 209Neuroinflammation and Neurodegeneration MechanismsSpinal Cord Injury ResearchImmune cells in cancer

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

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Fenn, A. M., Hall, J. C. E., Gensel, J. C., Popovich, P. G., Godbout, J. P.·2014·Journal of Neuroscience

DOI 10.1523/jneurosci.1146-14.2014PMC PMC4069360

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Abstract

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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Aged mice show deficient IL-4Rα expression, reduced arginase production, and impaired functional recovery following spinal cord injury compared with adult mice.
“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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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)
ORCID: Hall, J. C. E.
Gensel, J. C.
Popovich, P. G.
Godbout, J. P.
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
DOI: 10.1523/jneurosci.1146-14.2014
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 › Pathology and Forensic Medicine › 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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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

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