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Cited by 433Neuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology ResearchNeurological Disease Mechanisms and Treatments

Roles of neuropathology-associated reactive astrocytes: a systematic review

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Lawrence, Jill M., Schardien, Kayla, Wigdahl, Brian, Nonnemacher, Michael R.·2023·Acta Neuropathologica Communications
DOI 10.1186/s40478-023-01526-9PMC PMC10009953
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Abstract

In the contexts of aging, injury, or neuroinflammation, activated microglia signaling with TNF-α, IL-1α, and C1q induces a neurotoxic astrocytic phenotype, classified as A1, A1-like, or neuroinflammatory reactive astrocytes. In contrast to typical astrocytes, which promote neuronal survival, support synapses, and maintain blood–brain barrier integrity, these reactive astrocytes downregulate supportive functions and begin to secrete neurotoxic factors, complement components like C3, and chemokines like CXCL10, which may facilitate recruitment of immune cells across the BBB into the CNS. The proportion of pro-inflammatory reactive astrocytes increases with age through associated microglia activation, and these pro-inflammatory reactive astrocytes are particularly abundant in neurodegenerative disorders. As the identification of astrocyte phenotypes progress, their molecular and cellular effects are characterized in a growing array of neuropathologies.

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  • Microglia play a pivotal role by releasing factors such as TNF-α, IL-1β, and C1q, which trigger astrogliosis.

    “Microglia play a pivotal role by releasing factors such as tumor necrosis factor–α (TNF-α), interleukin-1β (IL-1β), and complement component 1q (C1q), which trigger astrogliosis (9, 15, 16).”

    From Varicose projection astrocytes: Conserved reactive cells in brain pathology (2026) · cites this paper as [9]

    The “Microglia activation” section says activated microglia secrete TNF-α, IL-1α, and C1q, and that these signals convert non-reactive astrocytes to a reactive phenotype. It supports the mechanism and two of the three named factors, but specifies IL-1α rather than the claim’s IL-1β. No page number is provided in our copy. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

  • The study accounted for established pathways of astrocyte-microglia cross-talk by using direct cytokine stimulation in 2D cultures lacking microglia and LPS-induced microglial activation in organoids.

    “Our approach accounted for established pathways of astrocyte-microglia cross-talk (8, 9, 15, 40), using direct cytokine stimulation (TNF-α and IL-1β) in 2D cultures lacking microglia and LPS-induced microglial activation in organoids (41)”

    From Varicose projection astrocytes: Conserved reactive cells in brain pathology (2026) · cites this paper as [9]

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Cited by

Sorted by citations

Authors
Lawrence, J. M., Schardien, K., Wigdahl, B., & Nonnemacher, M. R.
Affiliations
  • Drexel University (US)
  • Thomas Jefferson University (US)
Corresponding author
Nonnemacher, Michael R.
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2023-03-13
Volume
11
Issue
1
Pages
42-42
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-023-01526-9
PMC
PMC10009953
OpenAlex
W4324129387
Cited by
433
References
20
Citations by year
2026: 129 · 2025: 171 · 2024: 106 · 2023: 26 · 2022: 1
FWCI
11.25
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute of Neurological Disorders and Stroke (NS089435)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
reactive astrocytes, astrocyte activation, astrocyte-microglia interaction, neuroinflammation, aging, neurodegenerative diseases, TNF-α, IL-1α, C1q, complement C3, CXCL10, blood-brain barrier, astrocyte phenotype
MeSH terms
Astrocytes, Blood-Brain Barrier, Central Nervous System, Humans, Microglia, Chemokines, Neurotoxicity Syndromes

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