TY  - JOUR
AU  - Ravichandran, Kishore Aravind
AU  - Brosseron, Frederic
AU  - McManus, Róisín M
AU  - Ising, Christina
AU  - Görgen, Simon
AU  - Schmidt, Susanne V
AU  - Santarelli, Fracesco
AU  - Lee, Se Young
AU  - Jung, Hyuncheol
AU  - Chung, Won-Suk
AU  - Kim, Chan Hyuk
AU  - Ruiz Laza, Agustín
AU  - Ruiz de Almodóvar, Carmen
AU  - Ramirez, Alfredo
AU  - Latz, Eicke
AU  - Heneka, Michael T
TI  - Enhancing Tyro3 signaling ameliorates IL-1β production through STAT1 in Alzheimer's disease models.
JO  - Journal of leukocyte biology
VL  - 117
IS  - 12
SN  - 0741-5400
CY  - Tokyo
PB  - Oxford University Press
M1  - DZNE-2025-01359
SP  - qiaf157
PY  - 2025
AB  - 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.
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: pathology
KW  - Alzheimer Disease: genetics
KW  - Interleukin-1beta: biosynthesis
KW  - Interleukin-1beta: metabolism
KW  - Animals
KW  - Humans
KW  - Signal Transduction
KW  - Disease Models, Animal
KW  - STAT1 Transcription Factor: metabolism
KW  - Mice
KW  - Receptor Protein-Tyrosine Kinases: metabolism
KW  - Receptor Protein-Tyrosine Kinases: genetics
KW  - Amyloid beta-Peptides: metabolism
KW  - Inflammasomes: metabolism
KW  - THP-1 Cells
KW  - Proto-Oncogene Proteins: metabolism
KW  - Phosphorylation
KW  - Axl Receptor Tyrosine Kinase
KW  - Male
KW  - Mice, Inbred C57BL
KW  - Nitriles
KW  - Mice, Transgenic
KW  - AD (Other)
KW  - Alzheimer’s disease (Other)
KW  - IL-1β (Other)
KW  - NLRP3 (Other)
KW  - TAM receptors (Other)
KW  - Interleukin-1beta (NLM Chemicals)
KW  - STAT1 Transcription Factor (NLM Chemicals)
KW  - Receptor Protein-Tyrosine Kinases (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Inflammasomes (NLM Chemicals)
KW  - Proto-Oncogene Proteins (NLM Chemicals)
KW  - Axl Receptor Tyrosine Kinase (NLM Chemicals)
KW  - Tyro3 protein, mouse (NLM Chemicals)
KW  - TYRO3 protein, human (NLM Chemicals)
KW  - Nitriles (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41206011
DO  - DOI:10.1093/jleuko/qiaf157
UR  - https://pub.dzne.de/record/282601
ER  -