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Review
. 2017 Jan 27:8:43.
doi: 10.3389/fimmu.2017.00043. eCollection 2017.

The NLRP3 and Pyrin Inflammasomes: Implications in the Pathophysiology of Autoinflammatory Diseases

Carlos de Torre-Minguela  1 , Pablo Mesa Del Castillo  2 , Pablo Pelegrín  1
Affiliations
Review

The NLRP3 and Pyrin Inflammasomes: Implications in the Pathophysiology of Autoinflammatory Diseases

Carlos de Torre-Minguela et al. Front Immunol. .

Abstract

Inflammasomes are multiprotein complexes that critically control different aspects of innate and adaptive immunity. Among them we could highlight the release of pro-inflammatory cytokines that induce and maintain the inflammatory response. Usually, inflammasomes result from oligomerization of a nucleotide-binding domain-like receptor (NLR) after sensing different pathogenic or endogenous sterile dangerous signals; however, other proteins such as absent in melanoma 2, retinoic acid-inducible gene I, or pyrin could also form inflammasome platforms. Inflammasome oligomerization leads to caspase-1 activation and the processing and release of the pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18. Mutations in different inflammasomes are causative for multiple periodic hereditary syndromes or autoinflammatory diseases, characterized by acute systemic inflammatory flares not associated with infections, tumors, or autoimmunity. This review focuses on germline mutations that have been described in cryopyrin-associated periodic syndrome (CAPS) for NLRP3 or in familial Mediterranean fever (FMF) and pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) for MEFV. Besides the implication of inflammasomes in autoinflammatory syndromes, these molecular platforms are involved in the pathophysiology of different illnesses, including chronic inflammatory diseases, degenerative processes, fibrosis, or metabolic diseases. Therefore, drug development targeting inflammasome activation is a promising field in expansion.

Keywords: NLRP3; P2X7 receptor; cryopyrin-associated periodic syndrome; extracellular ATP; familial Mediterranean fever; inflammation; pyrin.

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Figures

Figure 1
Figure 1
Inflammasome sensors and activators. A wide variety of pathogenic ligands and intracellular mediators are involved in inflammasome assembly. NLRP1b responds to proteolytic cleavage on their N-terminal induced by lethal toxin of Bacillus anthracis. NLRP3 is a general sensor of cellular damage that responds to intracellular harm induced by pathogenic or sterile insults. NLRC4 recognizes bacterial proteins via NLR family-apoptosis inhibitory proteins (NAIPs) and can assemble inflammasomes with or without recruiting ASC, similar to NLRP1b. Absent in melanoma 2 (AIM2) and interferon-inducible protein 16 (IFI-16) sense dsDNA through their HIN-200 domains; meanwhile, RIG-1 activates caspase-1 through an inflammasome assembly after it detects ssRNA. Pyrin inflammasome is induced by bacterial toxins that modify RhoA GTPase. DAMPs, danger-associated molecular patterns; PAMPs, pathogen-associated molecular patterns; ssRNA, single strand RNA, dsDNA, double strand DNA.
Figure 2
Figure 2
Regulatory mechanisms of NLRP3 inflammasome assembly. The expression levels of NLRP3 are regulated by miR-223 in basal conditions but can be upregulated after cell recognition of pathogen-associated molecular patterns that induce NF-κB signaling pathway. The activation of NLRP3 by cellular damage signals as intracellular K+ decrease or reactive oxygen species (ROS) production requires a deubiquitylation of NLRP3 by BRCC3 and also their interaction with NEK7, only available during interphase. External signals, such as interferons (IFNs) or prostaglandin E2 (PGE2), negatively regulate NLRP3 through different mechanisms. The increase in nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) leads to the S-nitrosylation of NLRP3 impairing the assembly of the NLRP3 inflammasome. The increase of cyclic AMP (cAMP) induced by PGE2 signaling via prostaglandin E2 receptor 4 (EP4) activates the phosphorylation of NLRP3 reducing its oligomerization and increasing its ubiquitination to be degraded in autophagosomes. The interaction with pyrin domain-only proteins (POPs) can regulate NLRP3 inflammasome assembly by sequestering ASC or NLRP3.
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References

    1. Medzhitov R. Origin and physiological roles of inflammation. Nature (2008) 454:428–35.10.1038/nature07201 - DOI - PubMed
    1. Medzhitov R. Inflammation 2010: new adventures of an old flame. Cell (2010) 140:771–6.10.1016/j.cell.2010.03.006 - DOI - PubMed
    1. Compan V, Baroja-Mazo A, López-Castejón G, Gomez AI, Martínez CM, Angosto D, et al. Cell volume regulation modulates NLRP3 inflammasome activation. Immunity (2012) 37:487–500.10.1016/j.immuni.2012.06.013 - DOI - PubMed
    1. Ip WKE, Medzhitov R. Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation. Nat Commun (2015) 6:6931.10.1038/ncomms7931 - DOI - PMC - PubMed
    1. Pelegrin P. Inflammasome activation by danger signals. In: Couillin I, Petrilli V, Martinon F, editors. The Inflammasomes. Basel: Springer; (2011). p. 101–21.