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Inflammasomes in Myeloid Cells: Warriors Within

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  • Authors: Sushmita Jha1, W. June Brickey2, Jenny Pan-Yun Ting3
  • Editor: Siamon Gordon5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Bio-Sciences and Bio-Engineering, Indian Institute of Technology Jodhpur, Rajasthan, 342011, India; 2: Lineberger Comprehensive Cancer Center; 3: Lineberger Comprehensive Cancer Center; 4: Department of Genetics, The University of North Carolina, Chapel Hill, NC 27599; 5: Oxford University, Oxford, United Kingdom
  • Source: microbiolspec January 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.MCHD-0049-2016
  • Received 09 September 2016 Accepted 16 December 2016 Published 20 January 2017
  • Sushmita Jha, sushmitajha@gmail.com
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  • Abstract:

    The inflammasome is a large multimeric protein complex comprising an effector protein that demonstrates specificity for a variety of activators or ligands; an adaptor molecule; and procaspase-1, which is converted to caspase-1 upon inflammasome activation. Inflammasomes are expressed primarily by myeloid cells and are located within the cell. The macromolecular inflammasome structure can be visualized by cryo-electron microscopy. This complex has been found to play a role in a variety of disease models in mice, and several have been genetically linked to human diseases. In most cases, the effector protein is a member of the NLR (nucleotide-binding domain leucine-rich repeat-containing) or NOD (nucleotide oligomerization domain)-like receptor protein family. However, other effectors have also been described, with the most notable being AIM-2 (absent in melanoma 2), which recognizes DNA to elicit inflammasome function. This review will focus on the role of the inflammasome in myeloid cells and its role in health and disease.

  • Citation: Jha S, Brickey W, Ting J. 2017. Inflammasomes in Myeloid Cells: Warriors Within. Microbiol Spectrum 5(1):MCHD-0049-2016. doi:10.1128/microbiolspec.MCHD-0049-2016.

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/content/journal/microbiolspec/10.1128/microbiolspec.MCHD-0049-2016
2017-01-20
2017-09-26

Abstract:

The inflammasome is a large multimeric protein complex comprising an effector protein that demonstrates specificity for a variety of activators or ligands; an adaptor molecule; and procaspase-1, which is converted to caspase-1 upon inflammasome activation. Inflammasomes are expressed primarily by myeloid cells and are located within the cell. The macromolecular inflammasome structure can be visualized by cryo-electron microscopy. This complex has been found to play a role in a variety of disease models in mice, and several have been genetically linked to human diseases. In most cases, the effector protein is a member of the NLR (nucleotide-binding domain leucine-rich repeat-containing) or NOD (nucleotide oligomerization domain)-like receptor protein family. However, other effectors have also been described, with the most notable being AIM-2 (absent in melanoma 2), which recognizes DNA to elicit inflammasome function. This review will focus on the role of the inflammasome in myeloid cells and its role in health and disease.

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Figures

Image of FIGURE 1
FIGURE 1

NLRs function in healthy and dysregulated disease states in the human body.

Source: microbiolspec January 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.MCHD-0049-2016
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Image of FIGURE 2
FIGURE 2

NLRs have a conserved tripartite structure with an N-terminal effector domain, a central NBD, and C-terminal LRRs. The effector domains of NLRs may include acidic transactivation domain (AD), baculoviral inhibitory repeat (BIR)-like domain, caspase-recruitment domain (CARD), pyrin domain, or domain of unknown function (X). In general, NLRP1, NLRP3, NLRP6, NLRP7, NLRC4, NAIP, and AIM2 are known to form inflammasomes, while CIITA, NOD1, NOD2, NLRC3, NLRC5, NLRX1, NLRP10, and NLRP12 do not.

Source: microbiolspec January 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.MCHD-0049-2016
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Image of FIGURE 3
FIGURE 3

The NLRP3 inflammasome is activated in response to several PAMPs and DAMPs, including but not limited to nucleic acids, LPS, lipooligosaccharide (LOS), MDP, ATP, uric acid crystals, hyaluronan sulfate, heparan sulfate, β-amyloid, asbestos, and silica. NLRP3 inflammasome formation is a two-signal process. The first signal involves priming: LPS engagement of TLR4 leads to NF-κB activation, causing increased expression of NLRP3 and IL-1β (step 1). NLRP3 forms a multiprotein inflammasome complex with the adaptor ASC and procaspase-1. NLRP3 and ASC undergo deubiquitination prior to inflammasome assembly. After priming, canonical inflammasome activation requires a second signal. The second signal may be the release into the cytoplasm of mitochondrial factors such as ROS, mitochondrial DNA (mtDNA), or cardiolipin (step 2), potassium efflux (step 3), or lysosomal cathepsin release (step 4). After receiving the second signal, NLRP3 recruits ASC via pyrin-pyrin interactions. ASC utilizes its CARD domain to recruit procaspase-1 by CARD-CARD interactions, thus leading to processing of procaspase-1 to active caspase-1 (step 5). In turn, caspase-1 is critical for the processing and release of IL-1β and IL-18.

Source: microbiolspec January 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.MCHD-0049-2016
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