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@ARTICLE{Ravichandran:282601,
author = {Ravichandran, Kishore Aravind and Brosseron, Frederic and
McManus, Róisín M and Ising, Christina and Görgen, Simon
and Schmidt, Susanne V and Santarelli, Fracesco and Lee, Se
Young and Jung, Hyuncheol and Chung, Won-Suk and Kim, Chan
Hyuk and Ruiz Laza, Agustín and Ruiz de Almodóvar, Carmen
and Ramirez, Alfredo and Latz, Eicke and Heneka, Michael T},
title = {{E}nhancing {T}yro3 signaling ameliorates {IL}-1β
production through {STAT}1 in {A}lzheimer's disease models.},
journal = {Journal of leukocyte biology},
volume = {117},
number = {12},
issn = {0741-5400},
address = {Tokyo},
publisher = {Oxford University Press},
reportid = {DZNE-2025-01359},
pages = {qiaf157},
year = {2025},
abstract = {Neuroinflammation plays a vital role in determining the
trajectory of Alzheimer's disease (AD) progression. In the
AD brain, microglial exposure to pathological amyloid β
(Aβ42) and tau peptide aggregates results in an NLRP3
inflammasome-activated proinflammatory response that ranges
from mild to severe. Recently we have shown that dementia
subjects with higher levels of soluble TAM receptors Tyro3
and AXL in the cerebrospinal fluid indicated cognitive
protection. The molecular mechanism for this protective
effect of TAM receptors is unknown. Here, we identified a
beneficial role of TAM receptors using Tyro3-overexpressing
(Tyro3OE) and Axl-overexpressing THP-1 cells. In the Tyro3OE
cells, the levels of the proinflammatory cytokine IL-1β
were markedly decreased in the AD microenvironment (tau +
Aβ42) and the classical NLRP3 inflammasome model
(lipopolysaccharide [LPS] + nigericin) in comparison with
the control cells. This was mediated by increased STAT1
phosphorylation and reduced IL-1β transcription enhancer
C-EBP-β in Tyro3OE cells. The use of the JAK1/2 inhibitor
ruxolitinib reduced the phosphorylation of STAT1, leading to
a partial restoration of IL-1β in the Tyro3OE cells. Last,
we found a significantly reduced IL-1β in the brains of AD
mice that has activated TAM signaling through Gas6-α-Aβ
lentiviral injection. In summary, TAM receptor Tyro3
overexpression decreased AD-associated IL-1β release from
macrophages thereby uncovering a potential beneficial role
for TAM receptors during neuroinflammation in AD.},
keywords = {Alzheimer Disease: metabolism / Alzheimer Disease:
pathology / Alzheimer Disease: genetics / Interleukin-1beta:
biosynthesis / Interleukin-1beta: metabolism / Animals /
Humans / Signal Transduction / Disease Models, Animal /
STAT1 Transcription Factor: metabolism / Mice / Receptor
Protein-Tyrosine Kinases: metabolism / Receptor
Protein-Tyrosine Kinases: genetics / Amyloid beta-Peptides:
metabolism / Inflammasomes: metabolism / THP-1 Cells /
Proto-Oncogene Proteins: metabolism / Phosphorylation / Axl
Receptor Tyrosine Kinase / Male / Mice, Inbred C57BL /
Nitriles / Mice, Transgenic / AD (Other) / Alzheimer’s
disease (Other) / IL-1β (Other) / NLRP3 (Other) / TAM
receptors (Other) / Interleukin-1beta (NLM Chemicals) /
STAT1 Transcription Factor (NLM Chemicals) / Receptor
Protein-Tyrosine Kinases (NLM Chemicals) / Amyloid
beta-Peptides (NLM Chemicals) / Inflammasomes (NLM
Chemicals) / Proto-Oncogene Proteins (NLM Chemicals) / Axl
Receptor Tyrosine Kinase (NLM Chemicals) / Tyro3 protein,
mouse (NLM Chemicals) / TYRO3 protein, human (NLM Chemicals)
/ Nitriles (NLM Chemicals)},
cin = {AG Heneka / AG McManus / AG Latz},
ddc = {570},
cid = {I:(DE-2719)1011303 / I:(DE-2719)1013042 /
I:(DE-2719)1013024},
pnm = {353 - Clinical and Health Care Research (POF4-353) / 352 -
Disease Mechanisms (POF4-352) / 351 - Brain Function
(POF4-351)},
pid = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352 /
G:(DE-HGF)POF4-351},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41206011},
doi = {10.1093/jleuko/qiaf157},
url = {https://pub.dzne.de/record/282601},
}