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Cited by 23Spinal Cord Injury ResearchNeuroinflammation and Neurodegeneration MechanismsPhagocytosis and Immune Regulation

PI3K signaling promotes formation of lipid-laden foamy macrophages at the spinal cord injury site

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Ryan, Christine B., Choi, James S., Kang, Brian, Herr, Seth, Pereira, Claudia, Moraes, Carlos T., Al-Ali, Hassan, Lee, Jae K.·2024·Neurobiology of Disease
DOI 10.1016/j.nbd.2023.106370PMC PMC10804283
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Abstract

After spinal cord injury (SCI), infiltrating macrophages undergo excessive phagocytosis of myelin and cellular debris, forming lipid-laden foamy macrophages. To understand their role in the cellular pathology of SCI, investigation of the foamy macrophage phenotype in vitro revealed a pro-inflammatory profile, increased reactive oxygen species (ROS) production, and mitochondrial dysfunction. Bioinformatic analysis identified PI3K as a regulator of inflammation in foamy macrophages, and inhibition of this pathway decreased their lipid content, inflammatory cytokines, and ROS production. Macrophage-specific inhibition of PI3K using liposomes significantly decreased foamy macrophages at the injury site after a mid-thoracic contusive SCI in mice. RNA sequencing and in vitro analysis of foamy macrophages revealed increased autophagy and decreased phagocytosis after PI3K inhibition as potential mechanisms for reduced lipid accumulation. Together, our data suggest that the formation of pro-inflammatory foamy macrophages after SCI is due to the activation of PI3K signaling, which increases phagocytosis and decreases autophagy.

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  • PI3K-AKT signaling is a key regulator of lipid metabolism, and PI3K inhibitors block the accumulation of LDs in numerous studies and study models.

    “PI3K-AKT signaling is another key regulator of lipid metabolism, and PI3K inhibitors have been shown to efficiently block the accumulation of LDs in numerous studies and in several study models [9, 64, 65].”

    From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [65]

    The Results report that PI3K inhibitors reduced lipid-droplet accumulation in foamy macrophages, supporting the inhibitor finding in this study model. But the Results and Discussion identify PDK1, not Akt, as the likely downstream effector; Akt knockdown did not affect lipid accumulation. This paper alone does not establish inhibitor efficacy across numerous studies and models. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Ryan, C. B., Choi, J. S., Kang, B., Herr, S., Pereira, C., Moraes, C. T., Al-Ali, H., & Lee, J. K.
Affiliations
University of Miami (US)
Corresponding author
Lee, Jae K.
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2024-01
Volume
190
Pages
106370
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2023.106370
PMC
PMC10804283
OpenAlex
W4389262679
Cited by
23
References
8
Citations by year
2026: 9 · 2025: 11 · 2024: 3
FWCI
4.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • University of Miami
  • National Institutes of Health (1s10od023579-01)
  • Leonard M. Miller School of Medicine
  • National Institute of Neurological Disorders and Stroke (F31NS115225, R01NS081040)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
spinal cord injury, PI3K signaling, foam cells, lipid accumulation, phagocytosis, autophagy, reactive oxygen species, mitochondrial dysfunction, neuroinflammation, macrophage infiltration, myelin phagocytosis
MeSH terms
Animals, Lipids, Macrophages, Spinal Cord, Spinal Cord Injuries, Reactive Oxygen Species, Phosphatidylinositol 3-Kinases, Mice

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