Therapeutic Neutralization of the NLRP1 Inflammasome Reduces the Innate Immune Response and Improves Histopathology after Traumatic Brain Injury

Vaccari, Juan Pablo de Rivero; Lotocki, George; Alonso, Ofelia F.; Bramlett, Helen M.; Dietrich, W. Dalton; Keane, Robert W.

doi:10.1038/jcbfm.2009.46

Cited by 280 publications

(281 citation statements)

References 42 publications

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“…Of importance is the finding that the NLRP1 inflammasome was present in motor neurons of the spinal cord, indicating that neurons express an inflammatory complex. 6 Similar findings regarding inflammasome activation in neurons have been obtained after traumatic brain injury 5,74 and stroke. 4 Increased levels of NLRP1, ASC, and caspase-1 have also been reported in the CSF of traumatic brain injury patients and are associated with poor prognosis.…”

Section: Inflammasome Activation After Brain and Spinal Cord Injurysupporting

confidence: 67%

“…13 In this regard, immunoprecipitation experiments indicate protein-protein interactions are made between NLRP1, ASC, caspase-1, caspase-11, and XIAP in neuronal lysates of sham and spinal cord-injured and brain-injured rodents. 5,6 These studies indicate that the inflammasome components in the CNS are preassembled before activation; however, it is possible that additional inflammasome proteins are recruited into inflammasome complexes as the inflammatory response becomes exacerbated. It has been suggested that preassembly of inflammasome complexes in CNS cells facilitates a rapid triggering of the innate immune response after CNS trauma.…”

Section: The Nlrp1 Inflammasomementioning

confidence: 99%

“…Most of the inflammasomes described to date contain an NLR protein, namely NLRP1, NLRP2, NLRP3, NLRP6, NLRP7, NLRP12, or NLRC4 (NLR-and caspase-activating recruitment domain-containing 4). 2,3 However, only few inflammasomes have been described and characterized in the CNS: The NLRP1 inflammasome in neurons, [4][5][6] the NLRP2 inflammasome in astrocytes, 7 the NLRP3 inflammasome in microglia, [8][9][10] and the absent in melanoma-2 (AIM2) inflammasome in neurons ( Figure 1). 11 However, other inflammasome sensors (including NLRP3, NLRP6, NLRP12, and interferon-g-inducible protein 16) may form inflammasomes in the CNS, but convincing data have not been generated to support this idea.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

Vaccari¹,

Dietrich²,

Keane

2014

J Cereb Blood Flow Metab

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269

214

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The inflammasome is an intracellular multiprotein complex involved in the activation of caspase-1 and the processing of the proinflammatory cytokines interleukin-1b (IL-1b) and IL-18. The inflammasome in the central nervous system (CNS) is involved in the generation of an innate immune inflammatory response through IL-1 cytokine release and in cell death through the process of pyroptosis. In this review, we consider the different types of inflammasomes (NLRP1, NLRP2, NLRP3, and AIM2) that have been described in CNS cells, namely neurons, astrocytes, and microglia. Importantly, we focus on the role of the inflammasome after brain and spinal cord injury and cover the potential activators of the inflammasome after CNS injury such as adenosine triphosphate and DNA, and the therapeutic potential of targeting the inflammasome to improve outcomes after CNS trauma.

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Section: Inflammasome Activation After Brain and Spinal Cord Injurysupporting

confidence: 67%

Section: The Nlrp1 Inflammasomementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

Vaccari¹,

Dietrich²,

Keane

2014

J Cereb Blood Flow Metab

Self Cite

269

214

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“…Caspase-1 then processes pro-IL-1β to a mature form that is rapidly secreted from the cell (5). The activation of caspase-1 can also cause cell death (6).…”

mentioning

confidence: 99%

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

Dénes

Coutts

Lénárt

et al. 2015

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

222

219

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Inflammation that contributes to acute cerebrovascular disease is driven by the proinflammatory cytokine interleukin-1 and is known to exacerbate resulting injury. The activity of interleukin-1 is regulated by multimolecular protein complexes called inflammasomes. There are multiple potential inflammasomes activated in diverse diseases, yet the nature of the inflammasomes involved in brain injury is currently unknown. Here, using a rodent model of stroke, we show that the NLRC4 (NLR family, CARD domain containing 4) and AIM2 (absent in melanoma 2) inflammasomes contribute to brain injury. We also show that acute ischemic brain injury is regulated by mechanisms that require ASC (apoptosis-associated specklike protein containing a CARD), a common adaptor protein for several inflammasomes, and that the NLRP3 (NLR family, pyrin domain containing 3) inflammasome is not involved in this process. These discoveries identify the NLRC4 and AIM2 inflammasomes as potential therapeutic targets for stroke and provide new insights into how the inflammatory response is regulated after an acute injury to the brain.inflammation | inflammasome | cerebral ischemia | brain injury | cell death

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“…TLRs induce transcriptional activation of pro-IL-1β, which is proteolytically processed via inflammasome activation (16,17). Studies have shown that neutralization of inflammasome activity results in less severe tissue pathologies following thromboembolic stroke (18,19). Currently, the exact function, complex molecular mechanisms, and precise interaction between TLRs and inflammasomes in the development of retinal ischemic injury remain elusive.…”

mentioning

confidence: 99%

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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Therapeutic Neutralization of the NLRP1 Inflammasome Reduces the Innate Immune Response and Improves Histopathology after Traumatic Brain Injury

Cited by 280 publications

References 42 publications

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

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

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