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ß2-adrenoceptor agonist formoterol attenuates NLRP3 inflammasome activation and GSDMD-mediated pyroptosis in microglia through enhancing IκBα/NF-κB inhibition, SQSTM1/p62-dependent selective autophagy and ESCRT-III-mediated plasma membrane repair.
Erdem, Mehmet; Erdem, Seniz; Alver, Ahmet; Kiran, Tugba Raika; Karahan, Süleyman Caner.
Afiliación
  • Erdem M; Department of Medical Biochemistry, Faculty of Medicine, Malatya Turgut Özal University, Malatya 44900, Turkey; Department of Medical Biochemistry, Graduate School of Medical Science, Karadeniz Technical University, Trabzon 61080, Turkey. Electronic address: mehmet.erdem@ozal.edu.tr.
  • Erdem S; Department of Medical Biochemistry, Graduate School of Medical Science, Karadeniz Technical University, Trabzon 61080, Turkey; Department of Medical Biochemistry, Faculty of Medicine, Karadeniz Technical University, Trabzon 61080, Turkey.
  • Alver A; Department of Medical Biochemistry, Faculty of Medicine, Karadeniz Technical University, Trabzon 61080, Turkey.
  • Kiran TR; Department of Medical Biochemistry, Faculty of Medicine, Malatya Turgut Özal University, Malatya 44900, Turkey.
  • Karahan SC; Department of Medical Biochemistry, Faculty of Medicine, Karadeniz Technical University, Trabzon 61080, Turkey.
Mol Cell Neurosci ; 130: 103956, 2024 Sep.
Article en En | MEDLINE | ID: mdl-39097250
ABSTRACT
Microglia are immune cells that play important roles in the formation of the innate immune response within the central nervous system (CNS). The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multiple protein complex that is crucial for innate immunity, and excessive activation of the inflammasome for various reasons contributes to the pathogenesis of neurodegenerative diseases (NDs). ß2-adrenoceptor agonists have become the focus of attention in studies on NDs due to the high synthesis of ß2-adrenoceptors in the central nervous system (CNS). Promising results have been obtained from these studies targeting anti-inflammatory and neuroprotective effects. Formoterol is an effective, safe for long-term use, and FDA-approved ß2-adrenoceptor agonist with demonstrated anti-inflammatory features in the CNS. In this study, we researched the effects of formoterol on LPS/ATP-stimulated NLRP3 inflammasome activation, pyroptosis, NF-κB, autophagy, and ESCRT-III-mediated plasma membrane repair pathways in the N9 microglia cells. The results showed that formoterol, through the IκBα/NF-κB axis, significantly inhibited NLRP3 inflammasome activation, reduced the level of active caspase-1, secretion of IL-1ß and IL-18 proinflammatory cytokine levels, and the levels of pyroptosis. Additionally, we showed that formoterol activates autophagy, autophagosome formation, and ESCRT-III-mediated plasma membrane repair, which are significant pathways in the inhibition of NLRP3 inflammasome activation and pyroptosis. Our study suggests that formoterol efficaciously prevents the NLRP3 inflammasome activation and pyroptosis in microglial cells regulation through IκBα/NF-κB, autophagy, autophagosome formation, and ESCRT-III-mediated plasma membrane repair.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Autofagia / FN-kappa B / Microglía / Inflamasomas / Agonistas de Receptores Adrenérgicos beta 2 / Fumarato de Formoterol / Piroptosis / Proteína con Dominio Pirina 3 de la Familia NLR Límite: Animals Idioma: En Revista: Mol Cell Neurosci Asunto de la revista: BIOLOGIA MOLECULAR / NEUROLOGIA Año: 2024 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Autofagia / FN-kappa B / Microglía / Inflamasomas / Agonistas de Receptores Adrenérgicos beta 2 / Fumarato de Formoterol / Piroptosis / Proteína con Dominio Pirina 3 de la Familia NLR Límite: Animals Idioma: En Revista: Mol Cell Neurosci Asunto de la revista: BIOLOGIA MOLECULAR / NEUROLOGIA Año: 2024 Tipo del documento: Article