Interleukin 4 modulates microglia homeostasis and attenuates the early slowly progressive phase of amyotrophic lateral sclerosis
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Abstract Microglia activation is a commonly pathological hallmark of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), a devastating disorder characterized by a selective motor neurons degeneration. Whether such activation might represent a causal event rather than a secondary epiphenomenon remains elusive. Here, we show that CNS-delivery of IL-4—via a lentiviral-mediated gene therapy strategy—skews microglia to proliferate, inducing these cells to adopt the phenotype of slowly proliferating cells. Transcriptome analysis revealed that IL-4-treated microglia express a broad number of genes normally encoded by embryonic microglia. Since embryonic microglia sustain CNS development, we then hypothesized that turning adult microglia to acquire such phenotype via IL-4 might be an efficient in vivo strategy to sustain motor neuron survival in ALS. IL-4 gene therapy in SOD1G93A mice resulted in a general amelioration of clinical outcomes during the early slowly progressive phase of the disease. However, such approach did not revert neurodegenerative processes occurring in the late and fast progressing phase of the disease.
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This method of culturing microglia in vitro can model a significant component of the in vivo response.
“confirming that this method of culturing microglia in vitro can model a significant component of the in vivo response.”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [45]
Genes regulated by IL-4 in cultured primary microglia significantly overlap with genes regulated by IL-4 in microglia in the mouse spinal cord in vivo (Fisher's exact test P = 1.8e-12).
“we saw a significant overlap of genes regulated by IL-4 in the cultured primary microglia, compared with genes regulated by IL-4 in microglia in the mouse spinal cord in vivo (Fisher’s exact test P = 1.8e-12) (45)”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [45]
Anti-inflammatory processes mediated by IL-4 provide benefits in models representing early stages of neurodegenerative conditions such as AD and amyotrophic lateral sclerosis.
“Anti-inflammatory processes are associated with tissue repair, such as those mediated by IL-4, working through microglia and macrophages, and have been shown to provide benefits in models representing the early stages of neurodegenerative conditions, such as AD and amyotrophic lateral sclerosis, and other disorders related to cell death (45,72,73).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [45]
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Nikodémová, M., Small, A. L., Smith, S. M. C., Mitchell, G. S., & Watters, J. J. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.11.009 · Cited by 74 · see citing works
CCL23 Expression Is Induced by IL-4 in a STAT6-Dependent Fashion
Novak, H., Müller, A., Harrer, N. E., Günther, C., Carballido, J. M., & Woisetschläger, M. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.7.4335 · Cited by 52 · see citing works
MiR-30e and miR-181d control Radial Glia cell proliferation via HtrA1 modulation
Nigro, A., Menon, R., Bergamaschi, A., Clovis, Y. M., Baldi, A., Ehrmann, M., Comı, G., Tonelli, D. D. P., Farina, C., Martino, G., et al. (2012) · Cell Death and Disease · doi:10.1038/cddis.2012.98 · Cited by 45 · see citing works
Self-citationImmig, K., Gericke, M. T., Menzel, F., Merz, F., Krueger, M., Schiefenhövel, F., Lösche, A., Jäger, K., Hanisch, U., Biber, K. P. H., et al. (2014) · Glia · doi:10.1002/glia.22771 · Cited by 44 · see citing works
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Motor Neuron Death in ALS: Programmed by Astrocytes?
Pirooznia, S. K., Dawson, V. L., & Dawson, T. M. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.024 · Cited by 30 · see citing works
Interleukin 4 induces the apoptosis of mouse microglial cells by a caspase-dependent mechanism
Soria, J. A., Arroyo, D. S., Gaviglio, E. A., Rodriguez‐Galán, M. C., Wang, J. M., & Iribarren, P. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.05.010 · Cited by 26 · see citing works
Tada, S., Okuno, T., Hitoshi, Y., Yasui, T., Honorat, J. A., Takata, K., Koda, T., Shimagami, H., Choong, C., Namba, A., et al. (2014) · Journal of Neuroinflammation · doi:10.1186/s12974-014-0179-2 · Cited by 12 · see citing works
Interleukin-4 Expressed By Neoplastic Cells Provokes an Anti-Metastatic Myeloid Immune Response
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Microglia 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 · see citing works
Self-citationLiu, W., Taso, O., Wang, R., Bayram, S., Graham, A. C., Garcia-Reitboeck, P., Mallach, A., Andrews, W. D., Piers, T. M., Botia, J. A., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa209 · Cited by 214 · see citing works
“Antiinflammatory processes are associated with tissue repair, such as those mediated by IL-4, working through microglia and macrophages, and have been shown to provide benefits in models representing the early stages of neurodegenerative conditions, such as AD and amyotrophic lateral sclerosis, and other disorders rel…”
BackgroundMethodDysregulated phosphoinositide 3-kinase signaling in microglia: shaping chronic neuroinflammation
Chu, E., Mychasiuk, R., Hibbs, M. L., & Semple, B. D. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02325-6 · Cited by 152 · see citing works
- Authors
- Rossi, C., Cusimano, M., Zambito, M., Finardi, A., Capotondo, A., Garcia-Manteiga, J. M., Comi, G., Furlan, R., Martino, G., & Muzio, L.
- Corresponding author
- Muzio, Luca
- ORCID
- Venue
- Cell Death & Disease
- Published
- 2018-02-14
- Volume
- 9
- Issue
- 2
- Pages
- 250-250
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC5833860
- OpenAlex
- W2790138775
- Cited by
- 77
- References
- 94
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 7 · 2023: 8 · 2022: 10 · 2021: 17 · 2020: 14 · 2019: 5 · 2018: 2
- FWCI
- 6.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Funders
- Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- IL-4, microglia, amyotrophic lateral sclerosis, lentiviral gene therapy, microglial activation, microglial proliferation, motor neuron survival, SOD1 G93A mice, neurodegeneration, microglial transcriptome
- MeSH terms
- Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Disease Models, Animal, Gene Expression Regulation, Homeostasis, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Phenotype, Spinal Cord, Transplantation, Homologous, Genetic Therapy, Signal Transduction, Interleukin-4, Bone Marrow Transplantation, Microglia, Genes, Reporter, Disease Progression, Green Fluorescent Proteins, Mice, Transcriptome, Primary Cell Culture
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