The ketone body β-hydroxybutyrate does not inhibit synuclein mediated inflammasome activation in microglia

Deora, Vandana, Albornoz, Eduardo A., Zhu, Kevin, Woodruff, Trent M. and Gordon, Richard (2017) The ketone body β-hydroxybutyrate does not inhibit synuclein mediated inflammasome activation in microglia. Journal of Neuroimmune Pharmacology, 1-7. doi:10.1007/s11481-017-9754-5

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Author Deora, Vandana
Albornoz, Eduardo A.
Zhu, Kevin
Woodruff, Trent M.
Gordon, Richard
Title The ketone body β-hydroxybutyrate does not inhibit synuclein mediated inflammasome activation in microglia
Journal name Journal of Neuroimmune Pharmacology   Check publisher's open access policy
ISSN 1557-1890
1557-1904
Publication date 2017-08-23
Sub-type Article (original research)
DOI 10.1007/s11481-017-9754-5
Open Access Status Not yet assessed
Start page 1
End page 7
Total pages 7
Place of publication New York, NY, United States
Publisher Springer
Language eng
Subject 2801 Neuroscience (miscellaneous)
2723 Immunology and Allergy
2403 Immunology
3004 Pharmacology
Abstract Parkinson's disease (PD) is recognized as the most common neurodegenerative movement disorder and results in debilitating motor deficits. The accumulation and spread of neurotoxic synuclein aggregates in the form of Lewy bodies is a key pathological feature of PD. Chronic activation of the NLRP3 inflammasome by protein aggregates is emerging as a major pathogenic mechanism in progressive neurodegenerative disorders and is considered an important therapeutic target. Recently the ketone body, β-hydroxy butyrate (BHB), was shown to efficiently inhibit the NLRP3 inflammasome in macrophages, and in vivo models of inflammatory disease. Furthermore, BHB can readily cross the blood brain barrier suggesting that it could have therapeutic benefits for the management of PD. In this study, we evaluated if BHB could inhibit chronic microglial inflammasome activation induced by pathological fibrillar synuclein aggregates. Interestingly, we found that BHB treatment almost completely blocked all aspects of inflammasome activation and pyroptosis induced by ATP and monosodium urate (MSU) crystals, consistent with previously published reports in macrophages. Surprisingly however, BHB did not inhibit inflammasome activation and release of IL-1β or caspase-1 induced by synuclein fibrils. Our results demonstrate that BHB does not block the upstream pathways regulating inflammasome activation by synuclein fibrils and suggest that synuclein mediated inflammasome activation proceeds via distinct mechanisms compared to traditional NLRP3 activators such as ATP and MSU.
Keyword Inflammasome
Microglia; Synuclein
NLRP3
Parkinson’s; Neuroinflammation
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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Created: Thu, 07 Sep 2017, 13:51:22 EST by Richard Gordon on behalf of School of Biomedical Sciences