Caspase signalling controls microglia activation and neurotoxicity

Burguillos, Miguel Ángel; Deierborg, Tomas; Kavanagh, Edel; Persson, Annette; Hajji, Nabil; García-Quintanilla, Albert; Cano, Josefina; Brundin, Patrik; Englund, Elisabet; Venero, José L.; Joseph, Bertrand

doi:10.1038/nature09788

Cited by 498 publications

(444 citation statements)

References 46 publications

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“…In primary monocultures and microglia-neuron cultures, LPS exposure alone or in combination with IFN-γ for a "booster" triggers the massive release of proinflammatory and cytotoxic factors, such as TNF-α, IL-6, and nitric oxide (NO), finally resulting in neuronal death (8,(11)(12)(13)(14)(15)(16)(17)(18). Similar effects were observed in vivo after intracerebral administration of LPS (19)(20)(21).…”

supporting

confidence: 54%

TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ

Papageorgiou

Lewen

Galow

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

151

140

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Microglia (tissue-resident macrophages) represent the main cell type of the innate immune system in the CNS; however, the mechanisms that control the activation of microglia are widely unknown. We systematically explored microglial activation and functional microglia-neuron interactions in organotypic hippocampal slice cultures, i.e., postnatal cortical tissue that lacks adaptive immunity. We applied electrophysiological recordings of local field potential and extracellular K + concentration, immunohistochemistry, design-based stereology, morphometry, Sholl analysis, and biochemical analyses. We show that chronic activation with either bacterial lipopolysaccharide through Toll-like receptor 4 (TLR4) or leukocyte cytokine IFN-γ induces reactive phenotypes in microglia associated with morphological changes, population expansion, CD11b and CD68 up-regulation, and proinflammatory cytokine (IL-1β, TNF-α, IL-6) and nitric oxide (NO) release. Notably, these reactive phenotypes only moderately alter intrinsic neuronal excitability and gamma oscillations (30-100 Hz), which emerge from precise synaptic communication of glutamatergic pyramidal cells and fast-spiking, parvalbumin-positive GABAergic interneurons, in local hippocampal networks. Short-term synaptic plasticity and extracellular potassium homeostasis during neural excitation, also reflecting astrocyte function, are unaffected. In contrast, the coactivation of TLR4 and IFN-γ receptors results in neuronal dysfunction and death, caused mainly by enhanced microglial inducible nitric oxide synthase (iNOS) expression and NO release, because iNOS inhibition is neuroprotective. Thus, activation of TLR4 in microglia in situ requires concomitant IFN-γ receptor signaling from peripheral immune cells, such as T helper type 1 and natural killer cells, to unleash neurotoxicity and inflammation-induced neurodegeneration. Our findings provide crucial mechanistic insight into the complex process of microglia activation, with relevance to several neurologic and psychiatric disorders.hippocampus | microglia | neuronal activity | slice culture | Toll-like receptor

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supporting

confidence: 54%

TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ

Papageorgiou

Lewen

Galow

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

151

140

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“…processing in IOP-induced retinal damage, whereas inhibition of caspase-1 only partially reduced levels of IL-1β, implying that caspase-8 processed IL-1β via a caspase-1-dependent, NLRP1/NLPR3 pathway and a caspase-1-independent pathway. Unlike in vitro LPS stimulating caspase-3 activation in microglia (22), IOP-induced ischemia did not significantly drive caspase-3 activation in the early stage of acute glaucoma, suggesting that caspase-8-rather than caspase-3-induced inflammatory responses may be responsible for RGC death with elevated IOP in the early retinal damage of acute glaucoma. These results demonstrate that caspase-8 is a key link between TLR4 and inflammasomes in IL-1β processing and that it contributes to IOP-induced RGC death.…”

Section: Significancementioning

confidence: 90%

“…Recently, multiple nonapoptotic roles of caspase-8 have been uncovered, especially its neuroinflammatory functions (22,23,31). Microglia activation releases proinflammatory factors, which mediate the pathogenesis of CNS diseases, including those Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Caspase-8 is implicated as an initiator caspase in death receptor-induced signaling of apoptosis (20,21). Recent reports have uncovered novel nonapoptotic functions of caspase-8 and caspase-3, showing that they induce microglia neurotoxicity and the production of IL-1β without causing microglia death (22,23). However, the underlying mechanism of caspase-8 activation in promoting IL-1β secretion is unclear.…”

mentioning

confidence: 99%

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Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1β production in acute glaucoma

Chi

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

241

207

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Acute glaucoma is a sight-threatening condition characterized by a sudden and substantial rise in intraocular pressure (IOP) and consequent retinal ganglion cell (RGC) death. Angle closure glaucoma, a common cause of glaucoma in Asia that affects tens of millions of people worldwide, often presents acutely with loss of vision, pain, and high IOP. Even when medical and surgical treatment is available, acute angle closure glaucoma can cause permanent and irreversible loss of vision. Toll-like receptor 4 (TLR4) signaling has been previously implicated in the pathogenesis of IOP-induced RGC death, although the underlying mechanisms are largely unknown. In the present study, we used an acute IOP elevation/glaucoma model to investigate the underlying mechanism of RGC death. We found that TLR4 leads to increased caspase-8 expression; this elevation increases IL-1β expression and RGC death via a caspase-1-dependent pathway involving Nod-like receptor family, pyrin domain containing 1 (NLRP1)/NLRP3 inflammasomes and a caspase-1-independent pathway. We show that inhibition of caspase-8 activation significantly attenuates RGC death by down-regulating the activation of NLRP1 and NLRP3, thus demonstrating the pivotal role of caspase-8 in the TLR4-mediated activation of inflammasomes. These findings demonstrate collectively a critical role of caspase-8 in transducing TLR4-mediated IL-1β production and RGC death and highlight signal transduction in a caspase-1-dependent NLRP1/NLRP3 inflammasome pathway and a caspase-1-independent pathway in acute glaucoma. These results provide new insight into the pathogenesis of glaucoma and point to a treatment strategy.retinal ischemia/reperfusion injury | cell apoptosis A cute glaucoma is a significant cause of permanent vision loss and irreversible blindness worldwide (1). It is most common among people of Asian descent, in part due to their having a more crowded anterior chamber (2, 3). With a rapid increase in intraocular pressure (IOP) to levels exceeding retinal perfusion pressure, there is resulting retinal ischemia and retinal ganglion cell (RGC) death. Individuals with angle closure glaucoma are much more likely to lose vision and become blind than those with primary open-angle glaucoma (4). The precise mechanisms by which elevated IOP leads to RGC death are not well understood. Accumulating evidence suggests that overactivated microglia have pivotal roles in triggering neurotoxicity in the CNS, including retinal inflammatory responses (5, 6), by producing proinflammatory factors such as IL-1β. IL-1β production is tightly controlled as part of the innate immune response in the CNS (7).Toll-like receptors (TLRs) and Nod-like receptors (NLRs) are two key pattern recognition receptors (PRRs) in the initiation of the innate immune response (8-10). TLR4 has been shown to have a central role in retinal and CNS ischemia/reperfusion (I/R) injuries (11-13). Neuronal death following ischemic injury activates intense inflammation, which triggers TLR4 signaling. It has been demonstrated that ...

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“…Indeed, activated caspase-3 plays a key role in the regulation of microglia activation, and TLR-mediated caspase-3 activation correlates positively with neurotoxicity [40]. Priming of microglia with the neuronal tissue protein α-synuclein enhances TLR2-mediated responses to bacterial lipopeptides (Pam 3 Cys) including caspase-3 activation and CCL2 secretion [41].…”

Section: Discussionmentioning

confidence: 99%

Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

Bi¹,

Qiao²,

Bergelson³

et al. 2015

J Infect Dis.

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Background. Staphylococcus epidermidis causes late-onset sepsis in preterm infants. Staphylococcus epidermidis activates host responses in part via Toll-like receptor 2 (TLR2). Epidemiologic studies link bacteremia and neonatal brain injury, but direct evidence is lacking.Methods. Wild-type and TLR2-deficient (TLR2−/−) mice were injected intravenously with S. epidermidis at postnatal day 1 prior to measuring plasma and brain cytokine and chemokine levels, bacterial clearance, brain caspase-3 activation, white/gray matter volume, and innate transcriptome.Results. Staphylococcus epidermidis bacteremia spontaneously resolved over 24 hours without detectable bacteria in the cerebrospinal fluid (CSF). TLR2−/− mice demonstrated delayed S. epidermidis clearance from blood, spleen, and liver. Staphylococcus epidermidis increased the white blood cell count in the CSF, increased interleukin 6, interleukin 12p40, CCL2, and CXCL1 concentrations in plasma; increased the CCL2 concentration in the brain; and caused rapid (within 6 hours) TLR2-dependent brain activation of caspase-3 and TLR2-independent white matter injury.Conclusions. Staphylococcus epidermidis bacteremia, in the absence of bacterial entry into the CSF, impairs neonatal brain development. Staphylococcus epidermidis bacteremia induced both TLR2-dependent and -independent brain injury, with the latter occurring in the absence of TLR2, a condition associated with an increased bacterial burden. Our study indicates that the consequences of transient bacteremia in early life may be more severe than commonly appreciated, and our findings may inform novel approaches to reduce bacteremia-associated brain injury.

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Caspase signalling controls microglia activation and neurotoxicity

Cited by 498 publications

References 46 publications

TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ

TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ

Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1β production in acute glaucoma

Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

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