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Cited by 52Neuroinflammation and Neurodegeneration MechanismsGlaucoma and retinal disordersInflammasome and immune disorders

IGFBPL1 is a master driver of microglia homeostasis and resolution of neuroinflammation in glaucoma and brain tauopathy

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Pan, Li, Cho, Kin-Sang, Wei, Xin, Xu, Fuyi, Lennikov, Anton, Hu, Guangan, Tang, Jing, Guo, Shuai +13 more·2023·Cell Reports
DOI 10.1016/j.celrep.2023.112889PMC PMC10528709
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Abstract

Microglia shift toward an inflammatory phenotype during aging that is thought to exacerbate age-related neurodegeneration. The molecular and cellular signals that resolve neuroinflammation post-injury are largely undefined. Here, we exploit systems genetics methods based on the extended BXD murine reference family and identify IGFBPL1 as an upstream cis-regulator of microglia-specific genes to switch off inflammation. IGFBPL1 is expressed by mouse and human microglia, and higher levels of its expression resolve lipopolysaccharide-induced neuroinflammation by resetting the transcriptome signature back to a homeostatic state via IGF1R signaling. Conversely, IGFBPL1 deficiency or selective deletion of IGF1R in microglia shifts these cells to an inflammatory landscape and induces early manifestation of brain tauopathy and retinal neurodegeneration. Therapeutic administration of IGFBPL1 drives pro-homeostatic microglia and prevents glaucomatous neurodegeneration and vision loss in mice. These results identify IGFBPL1 as a master driver of the counter-inflammatory microglial modulator that presents an endogenous resolution of neuroinflammation to prevent neurodegeneration in eye and brain.

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  • Glaucomatous damage due to IOP elevation from microbead injections is irreversible in the absence of treatments.

    “The glaucomatous damage due to IOP elevation as a result of microbead injections has been shown to be irreversible in the absence of treatments by previous studies (Frankfort et al., 2013; Pan et al., 2023; and Supplementary Table S1).”

    From Sustained Vision Recovery by OSK Gene Therapy in a Mouse Model of Glaucoma (2023) · cites this paper as Pan et al., 2023

    The Results section (page unavailable in our copy) reports that microbead-induced IOP elevation caused visual-function losses in PBS-treated mice and that only about 50% of retinal ganglion cells survived at eight weeks. It does not establish that the damage is irreversible without treatment; the Introduction's description of glaucoma as a cause of irreversible blindness does not specifically establish that for this microbead model. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Pan, L., Cho, K.-S., Wei, X., Xu, F., Lennikov, A., Hu, G., Tang, J., Guo, S., Chen, J., Kriukov, E., Kyle, R., Elzaridi, F., Jiang, S., Dromel, P. A., Young, M., Baranov, P., Do, C.-W., Williams, R. W., Chen, J., Lu, L., & Chen, D. F.
Affiliations
  • Massachusetts Eye and Ear Infirmary (US)
  • Binzhou Medical University (CN)
  • Koch Institute for Integrative Cancer Research At MIT (US)
  • University of Tennessee Health Science Center (US)
Corresponding author
  • Lu, Lu
  • Chen, Dong Feng
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2023-08
Volume
42
Issue
8
Pages
112889
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2023.112889
PMC
PMC10528709
OpenAlex
W4385420216
Cited by
52
References
17
Citations by year
2026: 17 · 2025: 17 · 2024: 15 · 2023: 3
FWCI
5.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • PolyU Institutional Research Archive (Hong Kong Polytechnic University) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Hong Kong Polytechnic University (1-WZ25)
  • NEI (R01EY025250, R01EY031696)
  • Harvard NeuroDiscovery Center (NS104315, R01EY021200)
  • BrightFocus Foundation
  • National Institutes of Health
  • Glaucoma Foundation (P30EY03790)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
microglia, glaucoma, IGF1R signaling, microglial homeostasis, lipopolysaccharide-induced neuroinflammation, retinal neurodegeneration, age-related neurodegeneration, microglial transcriptome, BXD mouse strains, vision loss
MeSH terms
Neuroinflammatory Diseases, Animals, Brain, Homeostasis, Humans, Inflammation, Microglia, Insulin-Like Growth Factor Binding Proteins, Tauopathies, Tumor Suppressor Proteins, Mice

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.

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