{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T12:28:38Z","timestamp":1791808118674,"version":"4.3.4"},"reference-count":46,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Tay\u2013Sachs and Allied Diseases Association (NTSAD)","award":["26"],"award-info":[{"award-number":["26"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Sandhoff disease (SD) is a progressive neurodegenerative lysosomal storage disorder characterized by GM2 ganglioside accumulation as a result of mutations in the HEXB gene, which encodes the \u03b2-subunit of the enzyme \u03b2-hexosaminidase. Lysosomal storage of GM2 triggers inflammation in the CNS and periphery. The NLRP3 inflammasome is an important coordinator of pro-inflammatory responses, and we have investigated its regulation in murine SD. The NLRP3 inflammasome requires two signals, lipopolysaccharide (LPS) and ATP, to prime and activate the complex, respectively, leading to IL-1\u03b2 secretion. Peritoneal, but not bone-marrow-derived, macrophages from symptomatic SD mice, but not those from pre-symptomatic animals, secrete the cytokine following priming with LPS with no requirement for activation with ATP, suggesting that such NLRP3 deregulation is related to the extent of glycosphingolipid storage. Dysregulated production of IL-1\u03b2 was dependent upon caspase activity but not cathepsin B. We investigated the role of IL-1\u03b2 in SD pathology using two approaches: the creation of hexb\u2212\/\u2212Il1r1\u2212\/\u2212 double knockout mice or by treating hexb\u2212\/\u2212 animals with anakinra, a recombinant form of the IL-1 receptor antagonist, IL-1Ra. Both resulted in modest but significant extensions in lifespan and improvement of neurological function. These data demonstrate that IL-1\u03b2 actively participates in the disease process and provides proof-of-principle that blockade of the pro-inflammatory cytokine IL-1\u03b2 may provide benefits to patients.<\/jats:p>","DOI":"10.3390\/cells14010035","type":"journal-article","created":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T11:24:19Z","timestamp":1735730659000},"page":"35","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Dysregulation of the NLRP3 Inflammasome and Promotion of Disease by IL-1\u03b2 in a Murine Model of Sandhoff Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Nick","family":"Platt","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn","family":"Shepherd","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9845-5913","authenticated-orcid":false,"given":"David A.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2842-1275","authenticated-orcid":false,"given":"Kerri-Lee","family":"Wallom","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raashid","family":"Luqmani","sequence":"additional","affiliation":[{"name":"Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Windmill Road, Oxford OX3 7LD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant C.","family":"Churchill","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antony","family":"Galione","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7614-0403","authenticated-orcid":false,"given":"Frances M.","family":"Platt","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"136195","DOI":"10.1016\/j.neulet.2021.136195","article-title":"The GM2 gangliosidoses: Unlocking the mysteries of pathogenesis and treatment","volume":"764","author":"Toro","year":"2021","journal-title":"Neurosci. 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