2. Academic Validation
  3. Enhancing Tyro3 signaling ameliorates IL-1β production through STAT1 in Alzheimer's disease models

Enhancing Tyro3 signaling ameliorates IL-1β production through STAT1 in Alzheimer's disease models

  • J Leukoc Biol. 2025 Dec 1;117(12):qiaf157. doi: 10.1093/jleuko/qiaf157.
Kishore Aravind Ravichandran 1 2 3,  Frederic Brosseron 2 4,  Róisín M McManus 1 2,  Christina Ising 5,  Simon Görgen 1,  Susanne V Schmidt 1,  Fracesco Santarelli 1 2,  Se Young Lee 6,  Hyuncheol Jung 6,  Won-Suk Chung 6,  Chan Hyuk Kim 6,  Agustín Ruiz Laza 7 8,  Carmen Ruiz de Almodóvar 3,  Alfredo Ramirez 5 9,  Eicke Latz 1 2,  Michael T Heneka 1 2 10
Affiliations

Affiliations

  • 1 Department of Neuroimmunology, Institute of Innate Immunity, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.
  • 2 German Centre for Neurodegenerative Diseases (DZNE) Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.
  • 3 Institute for Neurovascular Cell Biology, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.
  • 4 Department of Neurodegenerative disease and Geriatric Psychiatry, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.
  • 5 CECAD-Cluster of Excellence, University of Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany.
  • 6 Department of Biological Sciences Korea, Korea Advanced Institute of Science and Technology, 291, Daehak-ro, Yuseong-gu, 34141 Daejeon, Republic of Korea.
  • 7 Research Centre and Memory Clinic, ACE Alzheimer Centre, Universitat Internacional de Catalunya, C/ Gran Via de Carles III, 85 bis, 08028 Barcelona, Spain.
  • 8 Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, C/ Monforte de Lemos, 3-5. Pabellón 11, Planta 0, Fuencarral-El Pardo, 28029 Madrid, Spain.
  • 9 Neurogenetics and Molecular Psychiatry, CECAD, University of Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany.
  • 10 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval Campus, 6, Avenue du Swing, Belvaux, L-4367 Esch-sur-Alzette, Luxembourg.
PMID: 41206011 DOI: 10.1093/jleuko/qiaf157
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

AD; Alzheimer’s disease; IL-1β; NLRP3; TAM receptors.

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