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

Vaccari, Juan Pablo de Rivero; Dietrich, W. Dalton; Keane, Robert W.

doi:10.1038/jcbfm.2013.227

Cited by 275 publications

(232 citation statements)

References 83 publications

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“…Central neuropathic pain is encountered in chronic neurodegenerative diseases, such as AD and MS, and in post-trauma states, such as spinal cord injury and traumatic brain injury. 1 Consistent with a role for inflammasomes in neuroinflammation, elevated production of IL-1b has been identified in injured CNS tissues after spinal cord injury or traumatic brain injury, 68 and in the brain tissues in patients with MS 69 and AD. 70 71 Notably, NALP1 inflammasome activation was observed in both microglia and astrocytes after spinal cord injury 51 or traumatic brain injury.…”

mentioning

confidence: 95%

The inflammasome as a target for pain therapy

Zhang¹,

Li²,

Li³

et al. 2016

British Journal of Anaesthesia

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The interleukin-1 family of cytokines are potent inducers of inflammation and pain. Proteolytic activation of this family of cytokines is under the control of several innate immune receptors that coordinate to form large multiprotein signalling platforms, termed inflammasomes. Recent evidence suggests that a wide range of inflammatory diseases, cancers, and metabolic and autoimmune disorders, in which pain is a common complaint, may be coordinated by inflammasomes. Activation of inflammasomes results in cleavage of caspase-1, which subsequently induces downstream initiation of several potent pro-inflammatory cascades. Therefore, it has been proposed that targeting inflammasome activity may be a novel and effective therapeutic strategy for these pain-related diseases. The purpose of this narrative review article is to provide the reader with an overview of the activation and regulation of inflammasomes and to investigate the potential therapeutic role of inflammasome inhibition in the treatment of diseases characterized by pain, including the following: complex regional pain syndrome, gout, rheumatoid arthritis, inflammatory pain, neuropathic pain, chronic prostatitis, chronic pelvic pain syndrome, and fibromyalgia. We conclude that the role of the inflammasome in pain-associated diseases is likely to be inflammasome subtype and disease specific. The currently available evidence suggests that disease-specific targeting of the assembly and activity of the inflammasome complex may be a novel therapeutic opportunity for the treatment of refractory pain in many settings.

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mentioning

confidence: 95%

The inflammasome as a target for pain therapy

Zhang¹,

Li²,

Li³

et al. 2016

British Journal of Anaesthesia

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“…5,52 Overactivation of microglia may induce collateral damage to salvageable neurons after TBI. 53 On the other hand, activation of microglia may also play a beneficial role in removing damaged cellular structures and remodeling synaptic networks in the late recovery phase after TBI. 54 Therefore, moderate inhibition of CMA might reduce microglial overactivation-induced collateral damage in the acute phase, whereas promoting CMA in the late recovery phase might facilitate brain repair and networking.…”

Section: Fig 2 Electron Micrographs Of Neocortical Neurons After Trmentioning

confidence: 99%

Chaperone-Mediated Autophagy after Traumatic Brain Injury

Park

Liu

Luo

et al. 2015

Journal of Neurotrauma

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Chaperone-mediated autophagy (CMA) and the ubiquitin-proteasomal system (UPS) are two major protein degradation systems responsible for maintaining cellular homeostasis, but how these two systems are regulated after traumatic brain injury (TBI) remains unknown. TBI produces primary mechanical damage that must be repaired to maintain neuronal homeostasis. The level of lysosomal-associated membrane protein type 2A (LAMP2A) is the hallmark of CMA activity. The level of polyubiquitinated proteins (ubi-proteins) reflects UPS activity. This study utilized a moderate fluid percussion injury model in rats to investigate the changes in CMA and the UPS after TBI. Induction of CMA was manifested by significant upregulation of LAMP2A and secondary lysosomes during the periods of 1-15 days of recovery after TBI. In comparison, the levels of ubiproteins were increased only moderately after TBI. The increases in the levels of LAMP2A and 70 kDa heat-shock protein for CMA after TBI were seen mainly in the secondary lysosome-containing fractions. Confocal and electron microscopy further showed that increased LAMP2A or lysosomes were found mainly in neurons and proliferated microglia. Because CMA and the UPS are two major routes for elimination of different types of cellular aberrant proteins, the consecutive activation of these two pathways may serve as a protective mechanism for maintaining cellular homeostasis after TBI.

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“…During pathologic conditions associated with large-scale cell death such as ischemia, oxidative stress, or neural trauma, astrocytes themselves can become inflammatory cells and demonstrate phagocytic activity (Fontana et al, 1984;Soos et al, 1998). Transformation of astrocytes into phagocytic and antigen-presenting cells (as evidenced by local increases of surface markers of inflammatory activation including major histocompatibility complex (MHC) class II receptors, toll-like receptors (TLRs), and intracellular immune receptor systems including the NOD-like protein 3 (NLRP3) or Rig-1-protein complex of the inflammasome) is triggered by local increases in concentrations of inflammatory cytokines such as interferon (IFN)-γ (de Rivero Vaccari et al, 2014, 2016bFarina et al, 2005Farina et al, , 2007. The inflammasome is an intracellular complex that senses danger-associated molecular patterns (DAMPs) such as ATP that are released during cellular stress.…”

Section: Immune Regulationmentioning

confidence: 99%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

362

299

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Increasing data indicate that inflammation and alterations in glutamate neurotransmission are two novel pathways to pathophysiology in mood disorders. The primary goal of this review is to illustrate how these two pathways may converge at the level of the glia to contribute to neuropsychiatric disease. We propose that a combination of failed clearance and exaggerated release of glutamate by glial cells during immune activation leads to glutamate increases and promotes aberrant extrasynaptic signaling through ionotropic and metabotropic glutamate receptors, ultimately resulting in synaptic dysfunction and loss. Furthermore, glutamate diffusion outside the synapse can lead to the loss of synaptic fidelity and specificity of neurotransmission, contributing to circuit dysfunction and behavioral pathology. This review examines the fundamental role of glia in the regulation of glutamate, followed by a description of the impact of inflammation on glial glutamate regulation at the cellular, molecular, and metabolic level. In addition, the role of these effects of inflammation on glia and glutamate in mood disorders will be discussed along with their translational implications.

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

Cited by 275 publications

References 83 publications

The inflammasome as a target for pain therapy

The inflammasome as a target for pain therapy

Chaperone-Mediated Autophagy after Traumatic Brain Injury

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

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