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Cited by 201Barrier Structure and Function StudiesNeuroinflammation and Neurodegeneration MechanismsTraumatic Brain Injury and Neurovascular Disturbances

Reactive astrocytes transduce inflammation in a blood-brain barrier model through a TNF-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin

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Kim, Hyosung, Leng, Kun, Park, Jinhee, Sorets, Alexander G., Kim, Suil, Shostak, Alena, Embalabala, Rebecca J., Mlouk, Kate +12 more·2022·Nature Communications
DOI 10.1038/s41467-022-34412-4PMC PMC9630454
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Abstract

Astrocytes are critical components of the neurovascular unit that support blood-brain barrier (BBB) function. Pathological transformation of astrocytes to reactive states can be protective or harmful to BBB function. Here, using a human induced pluripotent stem cell (iPSC)-derived BBB co-culture model, we show that tumor necrosis factor (TNF) transitions astrocytes to an inflammatory reactive state that causes BBB dysfunction through activation of STAT3 and increased expression of SERPINA3, which encodes alpha 1-antichymotrypsin (α1ACT). To contextualize these findings, we correlated astrocytic STAT3 activation to vascular inflammation in postmortem human tissue. Further, in murine brain organotypic cultures, astrocyte-specific silencing of Serpina3n reduced vascular inflammation after TNF challenge. Last, treatment with recombinant Serpina3n in both ex vivo explant cultures and in vivo was sufficient to induce BBB dysfunction-related molecular changes. Overall, our results define the TNF-STAT3-α1ACT signaling axis as a driver of an inflammatory reactive astrocyte signature that contributes to BBB dysfunction.

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  • DAA pathway phenotypes are associated with AD.

    “APOE4 derived iAstrocytes showed increased inflammatory protein expression including those associated with DAA pathway phenotypes in AD [42][43][44][45] .”

    From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [42]

    The Results section reports higher levels of inflammatory reactive astrocyte markers in the AD cohort than in age-matched asymptomatic controls. The paper also lists a study titled “Disease-associated astrocytes in Alzheimer’s disease and aging” in its References, but the passages do not identify the measured cells or proteins as a DAA pathway phenotype. (LLM, conf=0.79)

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Authors
Kim, H., Leng, K., Park, J., Sorets, A. G., Kim, S., Shostak, A., Embalabala, R. J., Mlouk, K., Katdare, K. A., Rose, I. V. L., Sturgeon, S. M., Neal, E. H., Ao, Y., Wang, S., Sofroniew, M. V., Brunger, J. M., McMahon, D. G., Schrag, M. S., Kampmann, M., & Lippmann, E. S.
Affiliations
  • Vanderbilt University (US)
  • University of California, San Francisco (US)
  • Vanderbilt University Medical Center (US)
  • University of California, Los Angeles (US)
Corresponding author
Lippmann, Ethan S.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-11-02
Volume
13
Issue
1
Pages
6581-6581
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-34412-4
PMC
PMC9630454
OpenAlex
W4308147217
Cited by
201
References
16
Citations by year
2026: 66 · 2025: 58 · 2024: 47 · 2023: 27 · 2022: 3
FWCI
12.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (R01 GM117650, R21 AG070859)
  • Chan Zuckerberg Initiative
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords
reactive astrocytes, blood-brain barrier dysfunction, TNF-α, STAT3 signaling, alpha-1-antichymotrypsin, vascular inflammation, neurovascular unit, astrocyte activation
MeSH terms
alpha 1-Antichymotrypsin, Animals, Astrocytes, Blood-Brain Barrier, Cells, Cultured, Humans, Inflammation, Tumor Necrosis Factor-alpha, STAT3 Transcription Factor, Mice, Induced Pluripotent Stem Cells

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