A Molecular Platform in Neurons Regulates Inflammation after Spinal Cord Injury

Vaccari, Juan Pablo de Rivero; Lotocki, George; Marcillo, Alexander; Dietrich, W. Dalton; Keane, Robert W.

doi:10.1523/jneurosci.0157-08.2008

Cited by 300 publications

(347 citation statements)

References 64 publications

(77 reference statements)

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“…The NLRP1 inflammasome in the brain and spinal cord comprises NLRP1, caspase-1, ASC, caspase-11, and the inhibitor of apoptosis proteinX-linked inhibitor of apoptosis protein (XIAP) 6 (Figure 1). This neuronal NLRP1 inflammasome differs in structure from the NLRP1 inflammasome described in peripheral macrophages in a number of ways: First, the NLRP1 inflammasome complex in neurons is preassembled in unstimulated neurons or in normal CNS tissues.…”

Section: The Nlrp1 Inflammasomementioning

confidence: 99%

“…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%

“…15 The NLRP1 inflammasome is associated with the inhibitor of apoptosis protein XIAP that may keep inflammasome expression in check ( Figure 1A). 6 Moreover, spinal cord injury (SCI)-induced activation of the inflammasome was found to be associated with cleavage of XIAP into smaller fragments. Cleavage of XIAP produces an N-terminal BIR1-2 fragment with reduced ability to inhibit caspases.…”

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 3 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

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: The Nlrp1 Inflammasomementioning

confidence: 99%

Section: The Nlrp1 Inflammasomementioning

confidence: 99%

Section: The Nlrp1 Inflammasomementioning

confidence: 99%

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

269

214

View full text Add to dashboard Cite

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“…Reduced intracellular K þ concentration is the primary trigger of caspase-1 activation (Munoz-Planillo et al, 2013). While some reports indicate that Panx1 channel opening is an obligatory part of both NLRP1 and NLRP3 inflammasome activation (de Rivero Vaccari et al, 2008;Pelegrin and Surprenant, 2006;Silverman et al, 2009), other groups have reported P2X7 receptor-induced IL-1b release, independent of Panx1 (Pelegrin et al, 2008;Qu et al, 2011). A further study postulated that Panx1 is responsible for the release of ATP from dying cells, upstream of P2X7 activation in the signaling cascade (Dahl and Keane, 2012).…”

Section: The Role Of P2x Receptors In Neuroinflammationmentioning

confidence: 99%

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

et al. 2016

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a b s t r a c tThe principle functions of neuroinflammation are to limit tissue damage and promote tissue repair in response to pathogens or injury. While neuroinflammation has utility, pathophysiological inflammatory responses, to some extent, underlie almost all neuropathology. Understanding the mechanisms that control the three stages of inflammation (initiation, propagation and resolution) is therefore of critical importance for developing treatments for diseases of the central nervous system. The purinergic signaling system, involving adenosine, ATP and other purines, plus a host of P1 and P2 receptor subtypes, controls inflammatory responses in complex ways. Activation of the inflammasome, leading to release of pro-inflammatory cytokines, activation and migration of microglia and altered astroglial function are key regulators of the neuroinflammatory response. Here, we review the role of P1 and P2 receptors in mediating these processes and examine their contribution to disorders of the nervous system. Firstly, we give an overview of the concept of neuroinflammation. We then discuss the contribution of P2X, P2Y and P1 receptors to the underlying processes, including a discussion of cross-talk between these different pathways. Finally, we give an overview of the current understanding of purinergic contributions to neuroinflammation in the context of specific disorders of the central nervous system, with special emphasis on neuropsychiatric disorders, characterized by chronic low grade inflammation or maternal inflammation. An understanding of the important purinergic contribution to neuroinflammation underlying neuropathology is likely to be a necessary step towards the development of effective interventions.

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NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage

Chen

et al. 2014

Annals of Neurology

234

208

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Objective The NLRP3 (NALP3, cryopyrin) inflammasome, a key component of the innate immune system, facilitates caspase-1 and interleukin (IL)–1β processing, which amplifies the inflammatory response. Here, we investigated whether NLRP3 knockdown decreases neutrophil infiltration, reduces brain edema, and improves neurological function in an intracerebral hemorrhage (ICH) mouse model. We also determined whether mitochondrial reactive oxygen species (ROS) governed by mitochondrial permeability transition pores (mPTPs) would trigger NLRP3 inflammasome activation following ICH. Methods ICH was induced by injecting autologous arterial blood (30μl) into a mouse brain. NLRP3 small interfering RNAs were administered 24 hours before ICH. A mPTP inhibitor (TRO-19622) or a specific mitochondria ROS scavenger (Mito-TEMPO) was coinjected with the blood. In naive animals, rotenone, which is a respiration chain complex I inhibitor, was applied to induce mitochondrial ROS production, and followed by TRO-19622 or Mito-TEMPO treatment. Neurological deficits, brain edema, enzyme-linked immunosorbent assay, Western blot, in vivo chemical cross-linking, ROS assay, and immunofluorescence were evaluated. Results ICH activated the NLRP3 inflammasome. NLRP3 knockdown reduced brain edema and decreased myeloper-oxidase (MPO) levels at 24 hours, and improved neurological functions from 24 to 72 hours following ICH. TRO-19622 or Mito-TEMPO reduced ROS, NLRP3 inflammasome components, and MPO levels following ICH. In naive animals, rotenone administration induced mPTP formation, ROS generation, and NLRP3 inflammasome activation, which were then reduced by TRO-19622 or Mito-TEMPO. Interpretation The NLRP3 inflammasome amplified the inflammatory response by releasing IL-1β and promoting neutrophil infiltration following ICH. Mitochondria ROS may be a major trigger of NLRP3 inflammasome activation. The results of our study suggest that the inhibition of the NLRP3 inflammasome may effectively reduce the inflammatory response following ICH.

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A Molecular Platform in Neurons Regulates Inflammation after Spinal Cord Injury

Cited by 300 publications

References 64 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

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage

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