Inflammasomes in Myeloid Cells: Warriors Within

Sushmita Jha; W. June Brickey; Jenny Pan-Yun Ting

doi:10.1128/microbiolspec.MCHD-0049-2016

Chapter 17 : Inflammasomes in Myeloid Cells: Warriors Within

Authors: Sushmita Jha¹, W. June Brickey², Jenny Pan-Yun Ting³

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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

Content Type: Monograph

Publication Year: 2017

Category: Microbial Genetics and Molecular Biology

Book DOI: 10.1128/9781555819194

Chapter DOI: 10.1128/microbiolspec.MCHD-0049-2016

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Abstract:

Inflammation is the body’s response to injury, pathogen exposure, and irritants. Pattern recognition receptors allow our body to recognize a diverse array of patterns generated during exposure to these insults. In 2002, the nucleotide-binding domain leucine-rich repeat-containing (NLR, also known as NOD-like receptor) gene family of pattern recognition receptors was discovered ( 1 – 3 ). While several members were already recognized at that point, reports of the entire NLR family provided a global view. In the past 15 years of research, the physiological relevance of these genes has been revealed to include a diverse variety of functions. Gene mutations in some of the family members have been linked to autoinflammatory diseases in humans ( Fig. 1 ). This association of mutations in NLR genes to autoinflammatory diseases indicates critical functions in the regulation of immunity and inflammation.

Citation: Jha S, Brickey W, Ting J. 2017. Inflammasomes in Myeloid Cells: Warriors Within, p 305-324. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0049-2016

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Inflammasomes in Myeloid Cells: Warriors Within

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Figure 1

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

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Figure 1

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

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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.

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Figure 2

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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.

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Figure 3

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