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Regions of microglial activation precede and predict areas of neuronal loss in <jats:styled-content style=\"fixed-case\">JNCL<\/jats:styled-content>; however, the functional role of activated microglia remains to be defined. The inflammasome is a key molecular pathway for activating pro\u2010<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101\u03b2 in microglia, and <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101\u03b2 is elevated in the brains of <jats:styled-content style=\"fixed-case\">JNCL<\/jats:styled-content> patients and can induce neuronal cell death. Here, we utilized primary microglia isolated from <jats:styled-content style=\"fixed-case\">CLN<\/jats:styled-content>3<jats:sup>\u0394ex7\/8<\/jats:sup> mutant and wild\u2010type (<jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content>) mice to examine the impact of <jats:italic><jats:styled-content style=\"fixed-case\">CLN<\/jats:styled-content>3<\/jats:italic> mutation on microglial activation and inflammasome function. Treatment with neuronal lysates and ceramide, a lipid intermediate elevated in the <jats:styled-content style=\"fixed-case\">JNCL<\/jats:styled-content> brain, led to inflammasome activation and <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101\u03b2 release in <jats:styled-content style=\"fixed-case\">CLN<\/jats:styled-content>3<jats:sup>\u0394ex7\/8<\/jats:sup> microglia but not <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content> cells, as well as increased expression of additional pro\u2010inflammatory mediators. Similar effects were observed following either <jats:styled-content style=\"fixed-case\">TNF<\/jats:styled-content>\u2010\u03b1 or <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101\u03b2 treatment, suggesting that <jats:styled-content style=\"fixed-case\">CLN<\/jats:styled-content>3<jats:sup>\u0394ex7\/8<\/jats:sup> microglia exist in primed state and hyper\u2010respond to several inflammatory stimuli compared to <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content> cells. <jats:styled-content style=\"fixed-case\">CLN<\/jats:styled-content>3<jats:sup>\u0394ex7\/8<\/jats:sup> microglia displayed constitutive caspase\u20101 activity that when blocked led to increased glutamate release that coincided with hemichannel opening. Conditioned medium from activated <jats:styled-content style=\"fixed-case\">CLN<\/jats:styled-content>3<jats:sup>\u0394ex7\/8<\/jats:sup> or <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content> microglia induced significant cell death in <jats:styled-content style=\"fixed-case\">CLN<\/jats:styled-content>3<jats:sup>\u0394ex7\/8<\/jats:sup> but not <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content> neurons, demonstrating that intrinsically diseased <jats:styled-content style=\"fixed-case\">CLN<\/jats:styled-content>3<jats:sup>\u0394ex7\/8<\/jats:sup> neurons are less equipped to withstand cytotoxic insults generated by activated microglia. Collectively, aberrant microglial activation may contribute to the pathological chain of events leading to neurodegeneration during later stages of <jats:styled-content style=\"fixed-case\">JNCL<\/jats:styled-content>.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc12385-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p>Juvenile neuronal ceroid lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in <jats:italic>CLN3<\/jats:italic>. Regions of microglial activation precede and predict areas of neuronal loss in JNCL; however, the functional role of activated microglia remains to be defined. In this report, primary microglia from CLN3<jats:sup>\u0394ex7\/8<\/jats:sup> mutant mice over\u2010produced numerous inflammatory cytokines in response to stimuli that are present in the JNCL brain, whereas wild\u2010type microglia were relatively non\u2010responsive. In addition, activated microglia induced significant cell death in CLN3<jats:sup>\u0394ex7\/8<\/jats:sup> but not wild\u2010type neurons, demonstrating that intrinsically diseased CLN3<jats:sup>\u0394ex7\/8<\/jats:sup> neurons are less equipped to withstand cytotoxic insults. Collectively, aberrant microglial activation may contribute to the pathological chain of events leading to neurodegeneration during later stages of JNCL.\n<\/jats:p>","DOI":"10.1111\/jnc.12385","type":"journal-article","created":{"date-parts":[[2013,8,7]],"date-time":"2013-08-07T02:12:55Z","timestamp":1375841575000},"page":"245-258","source":"Crossref","is-referenced-by-count":68,"title":["Microglia in juvenile neuronal ceroid lipofuscinosis are primed toward a pro\u2010inflammatory phenotype"],"prefix":"10.1111","volume":"127","author":[{"given":"Juan","family":"Xiong","sequence":"first","affiliation":[{"name":"Department of Pathology and Microbiology University of Nebraska Medical Center Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammy","family":"Kielian","sequence":"additional","affiliation":[{"name":"Department of Pathology and Microbiology University of Nebraska Medical Center Omaha Nebraska 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