View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Frontiers - Publisher Connector REVIEW published: 27 January 2017 doi: 10.3389/fimmu.2017.00043 The NLRP3 and Pyrin Inflammasomes: Implications in the Pathophysiology of Autoinflammatory Diseases Carlos de Torre-Minguela1, Pablo Mesa del Castillo1,2 and Pablo Pelegrín1* 1 Unidad de Inflamación Molecular, Instituto Murciano de Investigación Biosanitaria-Virgen de la Arrixaca (IMIB-Arrixaca), CIBERehd, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain, 2 Unidad de Reumatología Pediátrica, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain 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 Edited by: also form inflammasome platforms. Inflammasome oligomerization leads to caspase-1 José Hernández-Rodríguez, Hospital Clinic of Barcelona, activation and the processing and release of the pro-inflammatory cytokines, such as Spain interleukin (IL)-1β and IL-18. Mutations in different inflammasomes are causative for Reviewed by: multiple periodic hereditary syndromes or autoinflammatory diseases, characterized by Manel Juan, Hospital Clinic of Barcelona, Spain acute systemic inflammatory flares not associated with infections, tumors, or autoim- Dominic De Nardo, munity. This review focuses on germline mutations that have been described in cryopy- Walter and Eliza Hall Institute rin-associated periodic syndrome (CAPS) for NLRP3 or in familial Mediterranean fever of Medical Research, Australia (FMF) and pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) for *Correspondence: MEFV. Besides the implication of inflammasomes in autoinflammatory syndromes, these Pablo Pelegrín molecular platforms are involved in the pathophysiology of different illnesses, including [email protected] chronic inflammatory diseases, degenerative processes, fibrosis, or metabolic diseases. Specialty section: Therefore, drug development targeting inflammasome activation is a promising field in This article was submitted to expansion. Inflammation, a section of the journal Frontiers in Immunology Keywords: inflammation, NLRP3, pyrin, extracellular ATP, P2X7 receptor, cryopyrin-associated periodic syndrome, familial Mediterranean fever Received: 01 December 2016 Accepted: 11 January 2017 Published: 27 January 2017 Citation: DANGER SIGNALS, INFLAMMASOMES, AND THE de Torre-Minguela C, PHYSIOLOGICAL SIGNIFICANCE OF THE Mesa del Castillo P and Pelegrín P (2017) The NLRP3 and Pyrin INFLAMMATORY RESPONSE Inflammasomes: Implications in the Pathophysiology of Inflammation is the response of the innate immune system to a noxious stimulus, including infec- Autoinflammatory Diseases. tions or tissue damage (1, 2). Characterization of inflammasomes represents a considerable advance Front. Immunol. 8:43. in the understanding of the inflammatory molecular events that occur in response to infections, and doi: 10.3389/fimmu.2017.00043 importantly, to tissue damage in the absence of pathogens. Furthermore, inflammasome activation Frontiers in Immunology | www.frontiersin.org 1 January 2017 | Volume 8 | Article 43 de Torre-Minguela et al. NLRP3 and Pyrin in Autoinflammatory Diseases has also been attributed to changes on physiological homeostatic histone-binding properties in the nucleus, and in the extracellular parameters, such as changes in extracellular osmolarity (3, 4), milieu, HMGB1 engages the advanced glycation end-product- and virtually, any perturbation in homeostasis could generate a specific receptor in conjunction with toll-like receptors (TLR) local or systemic inflammatory response 1( , 2). Tissue damage to induce an inflammatory response 16( ). In conclusion, innate and alteration of the homeostatic parameters induce the release immunity mechanisms converge in producing an inflammatory of danger signals from the cells that activate the inflammasome response as a consequence of infection, tissue damage, or loss of in innate immune cells (5). Danger signals are usually referred as homeostasis. danger or damage-associated molecular patterns (DAMPs). The dual use of the term “danger” or “damage” in the acronym DAMP INFLAMMASOME SENSOR PROTEINS denotes that danger signals are not only released after damaging conditions but also in response to dangerous situations, such as The nucleotide-binding domain-like receptor (NLR) family forms during cellular environment alterations. In homeostasis, cells in the main group of proteins considered as inflammasome sensors. tissues are in a physiological “basal” state maintained by nutri- These proteins contain a pyrin domain (PYD) or a caspase activa- ents, oxygen, growth factors, and adherence to other cells and tion and recruitment domain (CARD). The presence of one of the extracellular matrix. Changes in environmental parameters these domains in the sensor protein is required to assemble the (temperature, osmolarity, oxygen, or pH) induce a cellular stress inflammasome. Additionally, other proteins with some of these response and the subsequent release of DAMPs. Stress is then structural domains can also form functional inflammasomes, recognized by tissue-resident macrophages, activating different like absent in melanoma 2 (AIM2) protein, interferon-inducible signaling pathways, including inflammasomes, and inducing protein 16 (IFI-16), retinoic acid-inducible gene I (RIG-I), and an inflammatory response aimed to restore tissue functionality pyrin (17) (Figure 1). during noxious conditions. This inflammatory response was There are different inflammasome sensors dedicated to rec- termed para-inflammation by Medzhitov 1( ). Deregulation of ognize the presence of cytosolic nucleic acids. AIM2 presents para-inflammation is intimately related with immunity and an N-terminal PYD and a C-terminal hematopoietic interferon involved in the pathogenesis of immune-mediated diseases, (IFN)-inducible nuclear protein with 200-amino acid repeat being the base for the chronic low-level inflammation associ- (HIN-200) domain. AIM2 is critical to respond against the infec- ated, for example, to type 2 diabetes (6). If homeostasis imbal- tion of different pathogens by forming an inflammasome after ance continues or is complicated with infection, cells become recognition of double-stranded DNA (dsDNA) in the cytoplasm necrotic inducing an acute inflammatory response that will by the HIN-200 domain (18–20). Interestingly, other nucleic damage the tissue (7). acid sensor protein called IFI-16 has two C-terminal HIN-200 Damage-associated molecular patterns are intracellular com- domains and one N-terminal PYD. Upon detection of dsDNA, ponents released to the extracellular milieu in response to cell IFI-16 triggers the IFN response as a component of the signaling stress or necrosis that activates different inflammatory pathways, pathway (21) and can also induce the assembly of inflammasome such as inflammasomes. Inflammasomes are multimeric complex with ulterior caspase-1 activation (22). RIG-I is also a sensor of innate immune receptors, activating caspase-1 and proteolytic for viral RNA that contains two CARD domains and is able to mechanisms involved in pro-inflammatory cytokines [interleu- assemble an inflammasome 23( ). However, it should be noted kin (IL)-1β and IL-18] (8). During cell stress, plasma membrane that additional studies are required to demonstrate that IFI-16 becomes permeable to ions, such as K+, or to intracellular and RIG-I can form an inflammasome. metabolites, such as the nucleotide adenosine triphosphate (ATP) The structure of the sensor protein family NLR presents a cen- or uric acid (1). One of the best characterized DAMP is ATP, since tral nucleotide-binding domain (NBD), and most of them have in physiological homeostatic conditions, ectonucleotidases main- a C-terminal leucine-rich repeat (LRR) domain. The N-terminal tain low extracellular ATP concentration, but during necrosis or protein domain is used to classify this group of proteins in NLRP inflammatory conditions, a high extracellular ATP concentra- if it contains a PYD domain or NLRC if it contains a CARD tion is reached, and the purinergic P2X7 receptor is activated in domain (24). Interestingly, the capacity for assembling inflam- macrophages (9–12). P2X7 receptor is a potent activator of the masome is a feature that has not been described for all members inflammasome in macrophages and other innate immune cells of the NLR family. These sensor proteins are also involved in (9). Leakage of cellular proteins with intracellular functions is other aspects of innate immune response by regulating diverse another example of DAMPs; the release of these proteins usu- non-inflammasome pathways. Indeed, NLRP12 can play a role as ally follows secretory pathways independent of the endoplasmic a negative regulator of NF-κB signaling (25) or modulating IL-4 reticulum (ER) and Golgi apparatus. Activation of caspase-1 production in T cells (26), and NLRP6 is a negative regulator of by inflammasomes controls the release of these intracellular mucosal immunity in the gut (27,