%0 Journal Article
%A Ravichandran, Kishore Aravind
%A Brosseron, Frederic
%A McManus, Róisín M
%A Ising, Christina
%A Görgen, Simon
%A Schmidt, Susanne V
%A Santarelli, Fracesco
%A Lee, Se Young
%A Jung, Hyuncheol
%A Chung, Won-Suk
%A Kim, Chan Hyuk
%A Ruiz Laza, Agustín
%A Ruiz de Almodóvar, Carmen
%A Ramirez, Alfredo
%A Latz, Eicke
%A Heneka, Michael T
%T Enhancing Tyro3 signaling ameliorates IL-1β production through STAT1 in Alzheimer's disease models.
%J Journal of leukocyte biology
%V 117
%N 12
%@ 0741-5400
%C Tokyo
%I Oxford University Press
%M DZNE-2025-01359
%P qiaf157
%D 2025
%X 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.
%K Alzheimer Disease: metabolism
%K Alzheimer Disease: pathology
%K Alzheimer Disease: genetics
%K Interleukin-1beta: biosynthesis
%K Interleukin-1beta: metabolism
%K Animals
%K Humans
%K Signal Transduction
%K Disease Models, Animal
%K STAT1 Transcription Factor: metabolism
%K Mice
%K Receptor Protein-Tyrosine Kinases: metabolism
%K Receptor Protein-Tyrosine Kinases: genetics
%K Amyloid beta-Peptides: metabolism
%K Inflammasomes: metabolism
%K THP-1 Cells
%K Proto-Oncogene Proteins: metabolism
%K Phosphorylation
%K Axl Receptor Tyrosine Kinase
%K Male
%K Mice, Inbred C57BL
%K Nitriles
%K Mice, Transgenic
%K AD (Other)
%K Alzheimer’s disease (Other)
%K IL-1β (Other)
%K NLRP3 (Other)
%K TAM receptors (Other)
%K Interleukin-1beta (NLM Chemicals)
%K STAT1 Transcription Factor (NLM Chemicals)
%K Receptor Protein-Tyrosine Kinases (NLM Chemicals)
%K Amyloid beta-Peptides (NLM Chemicals)
%K Inflammasomes (NLM Chemicals)
%K Proto-Oncogene Proteins (NLM Chemicals)
%K Axl Receptor Tyrosine Kinase (NLM Chemicals)
%K Tyro3 protein, mouse (NLM Chemicals)
%K TYRO3 protein, human (NLM Chemicals)
%K Nitriles (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41206011
%R 10.1093/jleuko/qiaf157
%U https://pub.dzne.de/record/282601