Microglia in juvenile neuronal ceroid lipofuscinosis are primed toward a pro-inflammatory phenotype

Juan Xiong, Tammy L Kielian

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Juvenile neuronal ceroid lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3. Regions of microglial activation precede and predict areas of neuronal loss in JNCL; however, the functional role of activated microglia remains to be defined. The inflammasome is a key molecular pathway for activating pro-IL-1β in microglia, and IL-1β is elevated in the brains of JNCL patients and can induce neuronal cell death. Here, we utilized primary microglia isolated from CLN3 Δex7/8 mutant and wild-type (WT) mice to examine the impact of CLN3 mutation on microglial activation and inflammasome function. Treatment with neuronal lysates and ceramide, a lipid intermediate elevated in the JNCL brain, led to inflammasome activation and IL-1β release in CLN3 Δex7/8 microglia but not WT cells, as well as increased expression of additional pro-inflammatory mediators. Similar effects were observed following either TNF-α or IL-1β treatment, suggesting that CLN3Δex7/8 microglia exist in primed state and hyper-respond to several inflammatory stimuli compared to WT cells. CLN3Δex7/8 microglia displayed constitutive caspase-1 activity that when blocked led to increased glutamate release that coincided with hemichannel opening. Conditioned medium from activated CLN3Δex7/8 or WT microglia induced significant cell death in CLN3Δex7/8 but not WT neurons, demonstrating that intrinsically diseased CLN3Δex7/8 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 JNCL. Juvenile neuronal ceroid lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3. 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 CLN3Δex7/8 mutant mice over-produced numerous inflammatory cytokines in response to stimuli that are present in the JNCL brain, whereas wild-type microglia were relatively non-responsive. In addition, activated microglia induced significant cell death in CLN3 Δex7/8 but not wild-type neurons, demonstrating that intrinsically diseased CLN3Δex7/8 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. Juvenile neuronal ceroid lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3. 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 CLN3Δex7/8 mutant mice over-produced numerous inflammatory cytokines in response to stimuli that are present in the JNCL brain, whereas wild-type microglia were relatively non-responsive. In addition, activated microglia induced significant cell death in CLN3Δex7/8 but not wild-type neurons, demonstrating that intrinsically diseased CLN3Δex7/8 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.

Original languageEnglish (US)
Pages (from-to)245-258
Number of pages14
JournalJournal of Neurochemistry
Volume127
Issue number2
DOIs
StatePublished - Oct 1 2013

Fingerprint

Ceroid
Neuronal Ceroid-Lipofuscinoses
Microglia
Phenotype
Chemical activation
Neurons
Cell death
Inflammasomes
Lysosomal Storage Diseases
Interleukin-1
Brain
Cell Death
Mutation
Cytokines
Caspase 1

Keywords

  • CLN3
  • IL-1β
  • caspase-1
  • inflammasome
  • juvenile Batten disease
  • microglia

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Microglia in juvenile neuronal ceroid lipofuscinosis are primed toward a pro-inflammatory phenotype. / Xiong, Juan; Kielian, Tammy L.

In: Journal of Neurochemistry, Vol. 127, No. 2, 01.10.2013, p. 245-258.

Research output: Contribution to journalArticle

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N2 - Juvenile neuronal ceroid lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3. Regions of microglial activation precede and predict areas of neuronal loss in JNCL; however, the functional role of activated microglia remains to be defined. The inflammasome is a key molecular pathway for activating pro-IL-1β in microglia, and IL-1β is elevated in the brains of JNCL patients and can induce neuronal cell death. Here, we utilized primary microglia isolated from CLN3 Δex7/8 mutant and wild-type (WT) mice to examine the impact of CLN3 mutation on microglial activation and inflammasome function. Treatment with neuronal lysates and ceramide, a lipid intermediate elevated in the JNCL brain, led to inflammasome activation and IL-1β release in CLN3 Δex7/8 microglia but not WT cells, as well as increased expression of additional pro-inflammatory mediators. Similar effects were observed following either TNF-α or IL-1β treatment, suggesting that CLN3Δex7/8 microglia exist in primed state and hyper-respond to several inflammatory stimuli compared to WT cells. CLN3Δex7/8 microglia displayed constitutive caspase-1 activity that when blocked led to increased glutamate release that coincided with hemichannel opening. Conditioned medium from activated CLN3Δex7/8 or WT microglia induced significant cell death in CLN3Δex7/8 but not WT neurons, demonstrating that intrinsically diseased CLN3Δex7/8 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 JNCL. Juvenile neuronal ceroid lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3. 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 CLN3Δex7/8 mutant mice over-produced numerous inflammatory cytokines in response to stimuli that are present in the JNCL brain, whereas wild-type microglia were relatively non-responsive. In addition, activated microglia induced significant cell death in CLN3 Δex7/8 but not wild-type neurons, demonstrating that intrinsically diseased CLN3Δex7/8 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. Juvenile neuronal ceroid lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3. 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 CLN3Δex7/8 mutant mice over-produced numerous inflammatory cytokines in response to stimuli that are present in the JNCL brain, whereas wild-type microglia were relatively non-responsive. In addition, activated microglia induced significant cell death in CLN3Δex7/8 but not wild-type neurons, demonstrating that intrinsically diseased CLN3Δex7/8 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.

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