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000282601 0247_ $$2doi$$a10.1093/jleuko/qiaf157
000282601 0247_ $$2pmid$$apmid:41206011
000282601 0247_ $$2ISSN$$a0741-5400
000282601 0247_ $$2ISSN$$a1938-3673
000282601 037__ $$aDZNE-2025-01359
000282601 041__ $$aEnglish
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000282601 1001_ $$0P:(DE-2719)9002244$$aRavichandran, Kishore Aravind$$b0$$eFirst author$$udzne
000282601 245__ $$aEnhancing Tyro3 signaling ameliorates IL-1β production through STAT1 in Alzheimer's disease models.
000282601 260__ $$aTokyo$$bOxford University Press$$c2025
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000282601 520__ $$aNeuroinflammation 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.
000282601 536__ $$0G:(DE-HGF)POF4-353$$a353 - Clinical and Health Care Research (POF4-353)$$cPOF4-353$$fPOF IV$$x0
000282601 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x1
000282601 536__ $$0G:(DE-HGF)POF4-351$$a351 - Brain Function (POF4-351)$$cPOF4-351$$fPOF IV$$x2
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000282601 650_7 $$2Other$$aAD
000282601 650_7 $$2Other$$aAlzheimer’s disease
000282601 650_7 $$2Other$$aIL-1β
000282601 650_7 $$2Other$$aNLRP3
000282601 650_7 $$2Other$$aTAM receptors
000282601 650_7 $$2NLM Chemicals$$aInterleukin-1beta
000282601 650_7 $$2NLM Chemicals$$aSTAT1 Transcription Factor
000282601 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aReceptor Protein-Tyrosine Kinases
000282601 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000282601 650_7 $$2NLM Chemicals$$aInflammasomes
000282601 650_7 $$2NLM Chemicals$$aProto-Oncogene Proteins
000282601 650_7 $$2NLM Chemicals$$aAxl Receptor Tyrosine Kinase
000282601 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aTyro3 protein, mouse
000282601 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aTYRO3 protein, human
000282601 650_7 $$2NLM Chemicals$$aNitriles
000282601 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000282601 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000282601 650_2 $$2MeSH$$aAlzheimer Disease: genetics
000282601 650_2 $$2MeSH$$aInterleukin-1beta: biosynthesis
000282601 650_2 $$2MeSH$$aInterleukin-1beta: metabolism
000282601 650_2 $$2MeSH$$aAnimals
000282601 650_2 $$2MeSH$$aHumans
000282601 650_2 $$2MeSH$$aSignal Transduction
000282601 650_2 $$2MeSH$$aDisease Models, Animal
000282601 650_2 $$2MeSH$$aSTAT1 Transcription Factor: metabolism
000282601 650_2 $$2MeSH$$aMice
000282601 650_2 $$2MeSH$$aReceptor Protein-Tyrosine Kinases: metabolism
000282601 650_2 $$2MeSH$$aReceptor Protein-Tyrosine Kinases: genetics
000282601 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000282601 650_2 $$2MeSH$$aInflammasomes: metabolism
000282601 650_2 $$2MeSH$$aTHP-1 Cells
000282601 650_2 $$2MeSH$$aProto-Oncogene Proteins: metabolism
000282601 650_2 $$2MeSH$$aPhosphorylation
000282601 650_2 $$2MeSH$$aAxl Receptor Tyrosine Kinase
000282601 650_2 $$2MeSH$$aMale
000282601 650_2 $$2MeSH$$aMice, Inbred C57BL
000282601 650_2 $$2MeSH$$aNitriles
000282601 650_2 $$2MeSH$$aMice, Transgenic
000282601 7001_ $$0P:(DE-2719)2810593$$aBrosseron, Frederic$$b1$$udzne
000282601 7001_ $$0P:(DE-2719)2811671$$aMcManus, Róisín M$$b2$$udzne
000282601 7001_ $$aIsing, Christina$$b3
000282601 7001_ $$aGörgen, Simon$$b4
000282601 7001_ $$aSchmidt, Susanne V$$b5
000282601 7001_ $$aSantarelli, Fracesco$$b6
000282601 7001_ $$aLee, Se Young$$b7
000282601 7001_ $$aJung, Hyuncheol$$b8
000282601 7001_ $$aChung, Won-Suk$$b9
000282601 7001_ $$aKim, Chan Hyuk$$b10
000282601 7001_ $$aRuiz Laza, Agustín$$b11
000282601 7001_ $$aRuiz de Almodóvar, Carmen$$b12
000282601 7001_ $$0P:(DE-2719)2812825$$aRamirez, Alfredo$$b13
000282601 7001_ $$0P:(DE-2719)2000062$$aLatz, Eicke$$b14$$udzne
000282601 7001_ $$0P:(DE-2719)2000008$$aHeneka, Michael T$$b15$$eLast author
000282601 773__ $$0PERI:(DE-600)2026833-6$$a10.1093/jleuko/qiaf157$$gVol. 117, no. 12, p. qiaf157$$n12$$pqiaf157$$tJournal of leukocyte biology$$v117$$x0741-5400$$y2025
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