Brain Pathology

Cover image for Vol. 27 Issue 2

Edited By: Seth Love

Impact Factor: 5.256

ISI Journal Citation Reports © Ranking: 2015: 6/79 (Pathology); 18/193 (Clinical Neurology); 33/256 (Neurosciences)

Online ISSN: 1750-3639

Mini-Symposium: Role of the Inflammasome in Brain Pathogenesis: A Potential Therapeutic Target?

  • What do we know about the inflammasome in humans?

    What do we know about the inflammasome in humans?

    Schematic illustration of the inflammasome complex. (A) The different steps involved in inflammasome formation. Three main components of the inflammasome (sensor, adaptor and caspase) are shown in the yellow rectangle. Some PRRs, such as NLRP1, can bind caspase directly (large, curvy arrow), without need of the adaptor. (B) The members of PRR superfamily as part of the inflammasome complex: directly (canonical) or indirectly (non-canonical). (C) The inflammasome pathways: canonical directly initiates caspase 1 activation, and non-canonical uses other caspases to facilitate inflammation.

  • What do we know about the inflammasome in humans?

    What do we know about the inflammasome in humans?

    Schematic representation of the two pathways and components involved in inflammasome activation. (A) The canonical pathway. Upon inflammasome formation, caspase 1 (red) directly activates cytokines IL1β, IL18 and pyroptotic gasdermin D. (B) The non-canonical pathways. (i) LPS can activate caspase 4/5 (blue) directly (large, curvy arrow) or via the TLR4 receptor, leading to gasdermin D maturation and pyroptosis. Cleaved Gasdermin D may then activate the NLRP3 inflammasome. (ii) Various pathogen signals (PAMPs), via CTL receptor, may initiate formation of the caspase 8 inflammasome (green). The product of both non-canonical inflammasomes is IL1β.

  • A brain in flame; do inflammasomes and pyroptosis influence stroke pathology?

    A brain in flame; do inflammasomes and pyroptosis influence stroke pathology?

    The detection of pro-inflammatory stimuli leads to the formation of macromolecular inflammasome complexes. Sensor molecules react to an array of damage associated molecular patterns (DAMPs) by recruiting a scaffold protein termed apoptosis-associated speck forming protein containing a CARD (ASC). ASC recruits the zymogen caspase-1 causing auto-cleavage and activation. Active caspase-1 imparts a pro-inflammatory lytic cell death termed pyroptosis through cleavage of gasdermin D (GSDMD). The N-terminus of GSDMD forms pores in the plasma membrane which allows passage of proinflammatory cytokines, such as interleukin (IL-) 1 and 18 that are also processed by inflammasomes. During stroke, inflammasomes contribute to brain injury through the spread of inflammation, leading to microglial activation and ingress of circulating immune cells. Inflammasomes themselves can be released during pyroptosis and propagate an inflammasome activation cascade within tissue.

  • Inflammasomes as therapeutic targets for Alzheimer's disease

    Inflammasomes as therapeutic targets for Alzheimer's disease

    Inflammation has an integral role in the pathogenesis of AD and can be influenced through a number of genetic and environmental factors. Amyloidopathy has been demonstrated to induce neurotoxic inflammation which has been shown to cause and propagate tauopathy. Neuronal damage caused by these processes could result in further inflammation in an unresolved feedback pattern. Many risk factors for AD such as inflammatory gene variants, brain injury, midlife obesity, diabetes, ageing and infection all have an inflammatory component; this supports the critical role inflammation has in AD and highlights the therapeutic potential of targeting inflammation.

  • Inflammasomes as therapeutic targets for Alzheimer's disease

    Inflammasomes as therapeutic targets for Alzheimer's disease

    Amyloid oligomers and monomers cause the expression of NLRP3 and proIL-1β through TLR mediated NFκB activation. The NLRP3 inflammasome is then activated by amyloid oligomers and fibrils through phagosomal disruption or cell surface K+ channels. Both pathways result in K+ efflux and cell swelling leading to Cl− efflux through VRAC. This, through an unknown mechanism, leads to deubiquitination of NLRP3 and ASC, and the binding of NEK7 to NLRP3 resulting in NLRP3 inflammasome activation. The NLRP3-ASC speck then recruits and activates caspase-1 which then cleaves gasdermin D and proIL-1β into their active forms. The N-terminus cleavage product of gasdermin D then forms pores in the cell membrane allowing the leaderless IL-1β to leave the cell.

  • What do we know about the inflammasome in humans?
  • What do we know about the inflammasome in humans?
  • A brain in flame; do inflammasomes and pyroptosis influence stroke pathology?
  • Inflammasomes as therapeutic targets for Alzheimer's disease
  • Inflammasomes as therapeutic targets for Alzheimer's disease

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