PMID- 37905154
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240210
DP  - 2023 Oct 16
TI  - Blocking Formation of Neurotoxic Reactive Astrocytes is Beneficial Following 
      Stroke.
LID - 2023.10.11.561918 [pii]
LID - 10.1101/2023.10.11.561918 [doi]
AB  - Microglia and astrocytes play an important role in the neuroinflammatory response 
      and contribute to both the destruction of neighboring tissue as well as the 
      resolution of inflammation following stroke. These reactive glial cells are 
      highly heterogeneous at both the transcriptomic and functional level. Depending 
      upon the stimulus, microglia and astrocytes mount a complex, and specific 
      response composed of distinct microglial and astrocyte substates. These substates 
      ultimately drive the landscape of the initiation and recovery from the adverse 
      stimulus. In one state, inflammation- and damage-induced microglia release tumor 
      necrosis factor (TNF), interleukin 1alpha (IL1alpha), and complement component 1q (C1q), 
      together 'TIC'. This cocktail of cytokines drives astrocytes into a neurotoxic 
      reactive astrocyte (nRA) substate. This nRA substate is associated with loss of 
      many physiological astrocyte functions (e.g., synapse formation and maturation, 
      phagocytosis, among others), as well as a gain-of-function release of neurotoxic 
      long-chain fatty acids which kill neighboring cells. Here we report that 
      transgenic removal of TIC led to reduction of gliosis, infarct expansion, and 
      worsened functional deficits in the acute and delayed stages following stroke. 
      Our results suggest that TIC cytokines, and likely nRAs play an important role 
      that may maintain neuroinflammation and inhibit functional motor recovery after 
      ischemic stroke. This is the first report that this paradigm is relevant in 
      stroke and that therapies against nRAs may be a novel means to treat patients. 
      Since nRAs are evolutionarily conserved from rodents to humans and present in 
      multiple neurodegenerative diseases and injuries, further identification of 
      mechanistic role of nRAs will lead to a better understanding of the 
      neuroinflammatory response and the development of new therapies.
FAU - Prescott, Kimberly
AU  - Prescott K
AUID- ORCID: 0000-0002-4652-6724
AD  - Department of Psychology, University of North Carolina Wilmington, 28428.
FAU - Munch, Alexandra E
AU  - Munch AE
AUID- ORCID: 0000-0002-9609-3277
AD  - Neuroscience Department, Stanford University, 94035.
FAU - Brahms, Evan
AU  - Brahms E
AUID- ORCID: 0000-0002-0073-3699
AD  - Department of Neurology and Neurological Sciences, Stanford School of Medicine, 
      94305.
FAU - Weigel, Maya M
AU  - Weigel MM
AUID- ORCID: 0000-0003-0557-5172
AD  - Neuroscience Department, Stanford University, 94035.
FAU - Inoue, Kenya
AU  - Inoue K
AUID- ORCID: 0009-0004-0760-5341
AD  - Department of Psychology, University of North Carolina Wilmington, 28428.
FAU - Buckwalter, Marion S
AU  - Buckwalter MS
AUID- ORCID: 0000-0003-2807-2447
AD  - Department of Neurology and Neurological Sciences, Stanford School of Medicine, 
      94305.
AD  - Department of Neurosurgery, Stanford School of Medicine, 94305.
FAU - Liddelow, Shane A
AU  - Liddelow SA
AUID- ORCID: 0000-0002-0840-1437
AD  - Neuroscience Institute, NYU Grossman School of Medicine, 10016.
AD  - Department of Neuroscience and Physiology, NYU Grossman School of Medicine, 
      10016.
AD  - Department of Ophthalmology, NYU Grossman School of Medicine, 10016.
AD  - Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, 
      10016.
FAU - Peterson, Todd C
AU  - Peterson TC
AUID- ORCID: 0000-0001-5441-6157
AD  - Department of Psychology, University of North Carolina Wilmington, 28428.
AD  - Department of Neurology and Neurological Sciences, Stanford School of Medicine, 
      94305.
LA  - eng
GR  - F32 NS089162/NS/NINDS NIH HHS/United States
GR  - R01 EY033353/EY/NEI NIH HHS/United States
PT  - Preprint
DEP - 20231016
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
PMC - PMC10614742
COIS- Conflict of interest statement: SAL declares ownership in AstronauTx Ltd, and 
      sits on the Scientific Advisory Board of the Global BioAccess Fund, Tamborine, 
      and Synapticure. The other authors declare no competing financial interests.
EDAT- 2023/10/31 06:42
MHDA- 2023/10/31 06:43
PMCR- 2023/10/30
CRDT- 2023/10/31 04:03
PHST- 2023/10/31 06:42 [pubmed]
PHST- 2023/10/31 06:43 [medline]
PHST- 2023/10/31 04:03 [entrez]
PHST- 2023/10/30 00:00 [pmc-release]
AID - 2023.10.11.561918 [pii]
AID - 10.1101/2023.10.11.561918 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2023 Oct 16:2023.10.11.561918. doi: 
      10.1101/2023.10.11.561918.