Dysregulation of the NLRP3 Inflammasome and Promotion of Disease by IL-1β in a Murine Model of Sandhoff Disease
Sandhoff disease (SD) is a progressive neurodegenerative lysosomal storage disorder characterized by GM2 ganglioside accumulation as a result of mutations in the <i>HEXB</i> gene, which encodes the β-subunit of the enzyme β-hexosaminidase. Lysosomal storage of GM2 triggers inflammation i...
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2025-01-01
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| author | Nick Platt Dawn Shepherd David A. Smith Claire Smith Kerri-Lee Wallom Raashid Luqmani Grant C. Churchill Antony Galione Frances M. Platt |
| author_facet | Nick Platt Dawn Shepherd David A. Smith Claire Smith Kerri-Lee Wallom Raashid Luqmani Grant C. Churchill Antony Galione Frances M. Platt |
| author_sort | Nick Platt |
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| description | Sandhoff disease (SD) is a progressive neurodegenerative lysosomal storage disorder characterized by GM2 ganglioside accumulation as a result of mutations in the <i>HEXB</i> gene, which encodes the β-subunit of the enzyme β-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-1β 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-1β was dependent upon caspase activity but not cathepsin B. We investigated the role of IL-1β in SD pathology using two approaches: the creation of <i>hexb</i><sup>−/−</sup><i>Il1r1</i><sup>−/−</sup> double knockout mice or by treating <i>hexb</i><sup>−/−</sup> 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-1β actively participates in the disease process and provides proof-of-principle that blockade of the pro-inflammatory cytokine IL-1β may provide benefits to patients. |
| format | Article |
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| institution | Kabale University |
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| publishDate | 2025-01-01 |
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| spelling | doaj-art-aa38bb2487e340e281ca9ed30ffe61112025-01-10T13:16:19ZengMDPI AGCells2073-44092025-01-011413510.3390/cells14010035Dysregulation of the NLRP3 Inflammasome and Promotion of Disease by IL-1β in a Murine Model of Sandhoff DiseaseNick Platt0Dawn Shepherd1David A. Smith2Claire Smith3Kerri-Lee Wallom4Raashid Luqmani5Grant C. Churchill6Antony Galione7Frances M. Platt8Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UKDepartment of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UKDepartment of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UKDepartment of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UKDepartment of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UKNuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Windmill Road, Oxford OX3 7LD, UKDepartment of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UKDepartment of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UKDepartment of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UKSandhoff disease (SD) is a progressive neurodegenerative lysosomal storage disorder characterized by GM2 ganglioside accumulation as a result of mutations in the <i>HEXB</i> gene, which encodes the β-subunit of the enzyme β-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-1β 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-1β was dependent upon caspase activity but not cathepsin B. We investigated the role of IL-1β in SD pathology using two approaches: the creation of <i>hexb</i><sup>−/−</sup><i>Il1r1</i><sup>−/−</sup> double knockout mice or by treating <i>hexb</i><sup>−/−</sup> 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-1β actively participates in the disease process and provides proof-of-principle that blockade of the pro-inflammatory cytokine IL-1β may provide benefits to patients.https://www.mdpi.com/2073-4409/14/1/35Sandhoff diseaseGM2 gangliosidosislysosomal storage diseaseNLRP3 inflammasomeIL-1βinflammation |
| spellingShingle | Nick Platt Dawn Shepherd David A. Smith Claire Smith Kerri-Lee Wallom Raashid Luqmani Grant C. Churchill Antony Galione Frances M. Platt Dysregulation of the NLRP3 Inflammasome and Promotion of Disease by IL-1β in a Murine Model of Sandhoff Disease Cells Sandhoff disease GM2 gangliosidosis lysosomal storage disease NLRP3 inflammasome IL-1β inflammation |
| title | Dysregulation of the NLRP3 Inflammasome and Promotion of Disease by IL-1β in a Murine Model of Sandhoff Disease |
| title_full | Dysregulation of the NLRP3 Inflammasome and Promotion of Disease by IL-1β in a Murine Model of Sandhoff Disease |
| title_fullStr | Dysregulation of the NLRP3 Inflammasome and Promotion of Disease by IL-1β in a Murine Model of Sandhoff Disease |
| title_full_unstemmed | Dysregulation of the NLRP3 Inflammasome and Promotion of Disease by IL-1β in a Murine Model of Sandhoff Disease |
| title_short | Dysregulation of the NLRP3 Inflammasome and Promotion of Disease by IL-1β in a Murine Model of Sandhoff Disease |
| title_sort | dysregulation of the nlrp3 inflammasome and promotion of disease by il 1β in a murine model of sandhoff disease |
| topic | Sandhoff disease GM2 gangliosidosis lysosomal storage disease NLRP3 inflammasome IL-1β inflammation |
| url | https://www.mdpi.com/2073-4409/14/1/35 |
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