Hypoxic induction of caspase-11/caspase-1/interleukin-1β in brain microglia

Kim, Nam Gon; Lee, Heasuk; Son, Eunyung; Kwon, Oh Young; Park, Jae Yong; Park, Jae Hoon; Cho, Gyeong Jae; Choi, Wan Sung; Suk, Kyoungho

doi:10.1016/s0169-328x(03)00135-9

Cited by 54 publications

(43 citation statements)

References 31 publications

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“…In the present study, expression of caspase-11 was observed in both microglial cells and neurons. It is suggested that caspase-11 in microglial cells and neurons contribute to IL-1␤ secretion (23) and apoptosis (24), respectively. Therefore both inflammatory process and apoptotic pathway seem to participate in LPS-induced SN dopaminergic neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Neurotoxic Effects of Lipopolysaccharide on Nigral Dopaminergic Neurons Are Mediated by Microglial Activation, Interleukin-1β, and Expression of Caspase-11 in Mice

Arai

Furuya

Yasuda³

et al. 2004

Journal of Biological Chemistry

118

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The endotoxin lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, selectively induces degeneration of substantia nigral (SN) dopaminergic neurons via activation of microglial cells in rats and mice. Caspase-11 plays a crucial role in LPS-induced septic shock in mice. We examined the mechanism of LPS neurotoxicity on SN dopaminergic neurons in C57BL/6 mice and caspase-11 knockout mice. Mice were stereotaxically injected with LPS into the SN on one side and vehicle into the SN of the other side. Immunohistochemistry, Western blotting analysis, enzyme-linked immunosorbent assay, and reverse transcriptase-PCR were performed to evaluate damage of SN dopaminergic neurons and activation of microglial cells. Intranigral injection of LPS at 1 or 3 g/l/site decreased tyrosine hydroxylase-positive neurons and increased microglial cells in the SN compared with the contralateral side injected with vehicle at days 7 and 14 post-injection in C57BL/6 mice. Intranigral injection of LPS at 3 g/l/site induced the expression of caspase-11 mRNA in the ventral midbrain at 6, 8, and 12 h postinjection, and the expression of caspase-11-positive cells in the SN at 8 and 12 h post-injection. Moreover, LPS at 3 g/l/site increased interleukin-1␤ content in the ventral midbrain at 12 and 24 h post-injection. LPS failed to elicit these responses in caspase-11 knockout mice. Our results indicate that the neurotoxic effects of LPS on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1␤, and caspase-11 expression in mice.Parkinson's disease (PD) 1 is histologically characterized by degeneration of dopaminergic neurons in the substantia nigra (SN). High concentrations of microglial cells are present in the SN, and activation of these cells has been observed in the SN of PD patients (1, 2). Recent studies postulated that activation of microglia and neuroinflammatory processes may contribute to the pathogenesis of PD (3, 4). Lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, is a potent inducer of inflammation and activator of microglia (5). Long term stimulation of innate immunity by LPS exacerbates motor neurodegeneration in a mouse model of amyotrophic lateral sclerosis, suggesting that the endotoxin LPS could be involved in neurodegenerative diseases caused by chronic peripheral bacterial infections especially in the presence of genetic or environmental risk factors (6).Dopaminergic neurons are far more sensitive to LPS-induced neurotoxicity than ␥-aminobutyric acidergic or serotonergic neurons, and intranigral injection of LPS induces selective and long lasting dopaminergic neurodegeneration via microglial activation in the SN (5). In PD patients, microglial activation, and selective and irreversible dopaminergic neurodegeneration in the SN are seen (1, 2); therefore intranigral injection of LPS is a suitable model for PD (5). With regard to the signal transduction by LPS, caspase-11 is considered to play a major role because resistance to LPS-induced sept...

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Section: Discussionmentioning

confidence: 99%

Neurotoxic Effects of Lipopolysaccharide on Nigral Dopaminergic Neurons Are Mediated by Microglial Activation, Interleukin-1β, and Expression of Caspase-11 in Mice

Arai

Furuya

Yasuda³

et al. 2004

Journal of Biological Chemistry

118

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“…When cultured brain microglia (BV-2 mouse microglial cells and rat primary microglial cultures) were exposed to transient hypoxia, a sequential set of events was triggered off; caspase-11 was activated followed by caspase-1 and secretion of functional IL-1b and IL-18 (Kim et al, 2003). This series of reactions observed at the molecular level was seen to be mediated via the p38 mitogen-activated protein kinase pathway.…”

Section: Therapeutic Modulation Of Inflammasomementioning

confidence: 99%

Inflammasome signaling at the heart of central nervous system pathology

Chakraborty

Kaushik

Gupta

et al. 2010

J of Neuroscience Research

169

111

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Neuroinflammation is a complex innate response of neural tissue against harmful effects of diverse stimuli viz., pathogens, damaged cells and irritants within the Central Nervous System (CNS). Studies show that multiple inflammatory mediators including cytokines, chemokines and prostaglandins are elevated in the Cerebrospinal Fluid (CSF) and in post-mortem brain tissues of patients with history of neuroinflammatory conditions as well as neurodegenerative disorders like Alzheimer's disease, Parkinson's disease and Multiple Sclerosis. The innate immunity mediators in the brain, namely microglia and astrocytes, express certain Pattern Recognition Receptors (PRRs), which are always on 'high-alert' for pathogens or other inflammatory triggers and participate in the assembly and activation of the inflammasome. The inflammasome orchestrates the activation of the precursors of proinflammatory caspases, which in turn, cleave the precursor forms of interleukin-1beta, IL-18 and IL-33 into their active forms; the secretion of which leads to a potent inflammatory response, and/or influences the release of toxins from glial and endothelial cells. Altered expression of inflammasome mediators can either promote or inhibit neurodegenerative processes. Therefore, modulating the inflammasome machinery seems a better combat strategy than summarily suppressing all inflammation in most neuroinflammatory conditions. In the current review we have surveyed the identified triggers and pathways of inflammasome activation and the following events which ultimately accomplish the innate inflammatory response in the CNS, with a goal to provide an analytical insight into disease pathogenesis that might provide cues for devising novel therapeutic strategies.

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“…In the rat model, cerebral blood flow (CBF) in the hemisphere ipsilateral to the carotid ligation decreased during hypoxia, but was restored immediately after the cessation of the hypoxic insult (Grow and Barks, 2002). Investigations using these rodent models revealed that proinflammatory molecules including cytokines (Hedtjarn et al, 2005a,b) and prostaglandin (PG) (Nogawa et al, 1997;Manabe et al, 2004), along with activated microglia/macrophages (Kim et al, 2003;Hedtjarn et al, 2004), are involved in the pathogenesis of HIE. It is known that PGs are upregulated in the ischemic brain (Nogawa et al, 1997) and that inhibition of their production is neuroprotective (Nogawa et al, 1997;Nakayama et al, 1998;Manabe et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin D₂Protects Neonatal Mouse Brain from Hypoxic Ischemic Injury

Taniguchi¹,

Mohri²,

Okabe-Arahori³

et al. 2007

J. Neurosci.

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Prostaglandin D 2 (PGD) is synthesized by hematopoietic PGD synthase (HPGDS) or lipocalin-type PGDS (L-PGDS), depending on the organ in which it is produced, and binds specifically to either DP 1 or DP 2 receptors. We investigated the role of PGD 2 in the pathogenesis of hypoxic-ischemic encephalopathy (HIE) in neonatal mice at postnatal day 7. In wild-type mice, hypoxia-ischemia increased PGD 2 production in the brain up to 90-fold compared with the level in sham-operated brains at 10 min after cessation of hypoxia. Whereas the size of the infarct was not changed in L-PGDS or DP 2 knock-out mouse brains compared with that in the wild-type HIE brains, it was significantly increased in HPGDS-L-PGDS double knock-out or DP 1 knock-out mice. The PGD 2 level in L-PGDS, HPGDS, and HPGDS-L-PGDS knock-out mice at 10 min of reoxygenation was 46, 7, and 1%, respectively, of that in the wild-type ones, indicating the infarct size to be in inverse relation to the amount of PGD 2 production. DP 1 receptors were exclusively expressed in endothelial cells after 1 h of reoxygenation, and cerebral blood flow decreased more rapidly after the onset of hypoxia and did not return to the baseline level after reoxygenation in HPGDS-L-PGDS knock-out mice. Endothelial cells were severely damaged in HPGDS-L-PGDS and DP 1 knock-out mice after 1 h of reoxygenation. In the human neonatal HIE brain, HPGDS-positive microglia were increased in number. In conclusion, it is probable that PGD 2 protected the neonatal brain from hypoxic-ischemic injury mainly via DP 1 receptors by preventing endothelial cell degeneration.

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Hypoxic induction of caspase-11/caspase-1/interleukin-1β in brain microglia

Cited by 54 publications

References 31 publications

Neurotoxic Effects of Lipopolysaccharide on Nigral Dopaminergic Neurons Are Mediated by Microglial Activation, Interleukin-1β, and Expression of Caspase-11 in Mice

Neurotoxic Effects of Lipopolysaccharide on Nigral Dopaminergic Neurons Are Mediated by Microglial Activation, Interleukin-1β, and Expression of Caspase-11 in Mice

Inflammasome signaling at the heart of central nervous system pathology

Prostaglandin D₂Protects Neonatal Mouse Brain from Hypoxic Ischemic Injury

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Hypoxic induction of caspase-11/caspase-1/interleukin-1β in brain microglia

Cited by 54 publications

References 31 publications

Neurotoxic Effects of Lipopolysaccharide on Nigral Dopaminergic Neurons Are Mediated by Microglial Activation, Interleukin-1β, and Expression of Caspase-11 in Mice

Neurotoxic Effects of Lipopolysaccharide on Nigral Dopaminergic Neurons Are Mediated by Microglial Activation, Interleukin-1β, and Expression of Caspase-11 in Mice

Inflammasome signaling at the heart of central nervous system pathology

Prostaglandin D2Protects Neonatal Mouse Brain from Hypoxic Ischemic Injury

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Prostaglandin D₂Protects Neonatal Mouse Brain from Hypoxic Ischemic Injury