Mechanisms of NLRP3 activation and pathology during neurodegeneration.

Autor: Jose S; UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Australia., Groves NJ; UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Australia., Roper KE; UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Australia., Gordon R; UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Australia; School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Australia. Electronic address: r.gordon1@uq.edu.au.
Jazyk: angličtina
Zdroj: The international journal of biochemistry & cell biology [Int J Biochem Cell Biol] 2022 Oct; Vol. 151, pp. 106273. Date of Electronic Publication: 2022 Aug 01.
DOI: 10.1016/j.biocel.2022.106273
Abstrakt: Inflammasomes are multiprotein complexes that are mainly present in resident and infiltrating immune cells in the central nervous system. Inflammasomes function as intracellular sensors of immunometabolic stress, infection and changes in the local microenvironment. Inflammasome assembly in response to these 'danger signals', triggers recruitment and cluster-dependent activation of caspase-1 and the subsequent proteolytic activation of inflammatory cytokines such as interleukin-1β and interleukin-18. This is typically followed by a form of inflammatory cell death through pyroptosis. Since the discovery of inflammasomes in 2002, they have come to be recognized as central regulators of acute and chronic inflammation, a hallmark of progressive neurological diseases. Indeed, over the last decade, extensive inflammasome activation has been found at the sites of neuropathology in all progressive neurodegenerative diseases. Disease-specific misfolded protein aggregates which accumulate in neurodegenerative diseases, such as alpha synuclein or beta amyloid, have been found to be important triggers of NLRP3 inflammasome activation in the central nervous system. Together, these discoveries have transformed our understanding of how chronic inflammation is triggered and sustained in the central nervous system, and how it can contribute to neuronal death and disease progression in age-related neurodegenerative diseases. Therapeutic strategies around inhibition of NLRP3 activation in the central nervous system are already being evaluated to determine their effectiveness to slow progressive neurodegeneration. This review summarizes current understanding of inflammasomes in the most prevalent neurodegenerative diseases and discusses current knowledge gaps and inflammasome inhibition as a therapeutic strategy.
Competing Interests: Conflicts of Interest The authors declare no conflicts of interest.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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