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Anecdotal reports from paediatricians indicate a more severe neurodegeneration in MPS IIIA patients, following infection, suggesting inflammation as a potential driver of neuropathology. To test this hypothesis, we performed acute studies in which WT and MPS IIIA mice were challenged with the TLR3-dependent viral mimetic poly(I:C). The challenge with an acute high poly(I:C) dose exacerbated systemic and brain cytokine expression, especially IL-1\u03b2 in the hippocampus. This was accompanied by an increase in caspase-1 activity within the brain of MPS IIIA mice with concomitant loss of hippocampal GFAP and NeuN expression. Similar levels of cell damage, together with exacerbation of gliosis, were also observed in MPS IIIA mice following low chronic poly(I:C) dosing. While further investigation is warranted to fully understand the extent of IL-1\u03b2 involvement in MPS IIIA exacerbated neurodegeneration, our data robustly reinforces our previous findings, indicating IL-1\u03b2 as a pivotal catalyst for neuropathological processes in MPS IIIA.<\/jats:p>","DOI":"10.1038\/s44321-024-00092-4","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T11:03:35Z","timestamp":1718708615000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Systemic immune challenge exacerbates neurodegeneration in a model of neurological lysosomal disease"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3726-9911","authenticated-orcid":false,"given":"Oriana","family":"Mandolfo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Parker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c8lia","family":"Aguado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1016-5324","authenticated-orcid":false,"given":"Yuko","family":"Ishikawa Learmonth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai Yin","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"O\u2019Leary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Ellison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6656-6328","authenticated-orcid":false,"given":"Gabriella","family":"Forte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaun","family":"Wood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Searle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4150-3299","authenticated-orcid":false,"given":"Rebecca J","family":"Holley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herv\u00e9","family":"Boutin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9708-1112","authenticated-orcid":false,"given":"Brian W","family":"Bigger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,18]]},"reference":[{"key":"92_CR1","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1111\/acel.12409","volume":"15","author":"E Aflaki","year":"2016","unstructured":"Aflaki E, Moaven N, Borger DK, Lopez G, Westbroek W, Chae JJ, Marugan J, Patnaik S, Maniwang E, Gonzalez AN et al (2016) Lysosomal storage and impaired autophagy lead to inflammasome activation in Gaucher macrophages. 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