Elsevier

Cytokine & Growth Factor Reviews

Volume 22, Issues 5–6, October–December 2011, Pages 257-276
Cytokine & Growth Factor Reviews

Survey
NOD-like receptors and the innate immune system: Coping with danger, damage and death

https://doi.org/10.1016/j.cytogfr.2011.09.003Get rights and content

Abstract

Members of the family of NOD-like receptors (NLRs) play essential roles in innate immunity by detecting intracellular ‘pathogen-associated molecular patterns’ (PAMPs) and ‘danger-associated molecular patterns’ (DAMPs). These molecules reveal the presence of pathogenic infection, abiotic stress, environmental insults, cellular damage, and cell death. NLR family members can be divided in two functional groups. One group consists of intracellular receptors, such as NLRP1, NLRP3, NLRP6 and NLRC4, which mediate the assembly of inflammasome complexes leading to the activation of procaspase-1. The second group includes members such as NOD1 and NOD2, and mediates the assembly of complexes that activate MAPK and NF-κB signaling pathways. We review the roles of NLR family members in health and disease, with emphasis on the signaling mechanisms in cell death and inflammation.

Introduction

Protection of an organism against harmful internal and external insults relies on the ability of the innate immune system to discriminate between what is dangerous and what is not. Innocuous signals are largely normal host proteins and commensal bacteria that have induced tolerance, whereas danger signals include pathogens, host-derived signals of cellular stress or danger, and environmental insults. Such threats are recognized by a number of germline-encoded danger-sensing receptors (DSRs) that detect conserved pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). The main objective of this ‘first line of defense’ is to mount a rapid but non-specific response that keeps the challenge in check. In addition, the innate immune response also regulates and directs the activation of the more specific adaptive immune system.

Hematopoietic cells, including macrophages, dendritic cells and neutrophils, as well as non-hematopoietic cells such as epithelial cells, contribute to this host-defense system by expressing DSRs. Different DSRs have been classified into families according to their subcellular localization, molecular structure, and recognition repertoire. Members of the Toll-like receptor (TLR) family and C-type lectin receptor (CLR) family are transmembrane receptors that line the plasma and endosomal membranes to survey the extracellular environment and the endosomes for the presence of PAMPs and DAMPs [1], [2]. Intracellular monitoring, which is critical when insults evade extracellular surveillance, is performed by the broad-spectrum PAMP- and DAMP-sensing nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), the viral RNA-sensing RIG-like helicase receptors (RLRs), and the cytosolic DNA sensors, RNA polymerase III, DAI, and absent-in-melanoma 2 (AIM2) [3], [4], [5]. When these receptors bind their agonists, they trigger an innate immune response by engaging specific signaling cascades. These signaling cascades lead to the production of certain cytokines and chemokines by activating transcription factors such as NF-κB, AP-1, Elk-1, ATF2, p53 and members of the interferon regulatory factor (IRF) family [6], [7], [8]. Chemokines, such as IL-8, MCP-1 and KC, attract other immune-regulatory cells, including neutrophils, monocytes and leukocytes, to the endangered area, while cytokines such as interleukin (IL)-1β, IL-6, IL-18 and tumor necrosis factor (TNF) determine how the cell responds.

This review focuses on the NLR family, whose members contribute to innate immunity by participating in multiple cellular processes, including inflammasome assembly to activate procapase-1 for the processing of IL-1β and IL-18 [3], caspase-1 dependent pyroptotic cell death [9], activation of NF-κB and MAPK signaling pathways to induce transcription of cytokines and chemokines [10], autophagy [11], [12], and control of type I interferon (IFN) signaling [13], [14], [15]. So far, in silico work has identified 22 human and 34 mouse NLR members [16], [17]. The defining feature of NLRs is the presence of a NACHT domain (domain present in NAIP, CIITA, HET-E, and TP-1), which is generally followed by a series of leucine-rich repeats (LRRs) [18] (Fig. 1). As a member of the AAA+ superfamily of nucleotide-binding and oligomerization domains, the NACHT domain mediates NLR oligomerization, whereas the LRRs form the sensing module [19]. In addition, apart from NLRX1, all NLRs contain an N-terminal effector module, which is used to classify them into four subfamilies [18]. The NLRA subfamily contains only the founder NLR, CIITA, because it is the only NLR with an acidic transactivation domain (Fig. 1). This domain plays an essential role in the transcriptional regulation of MHC Class II genes [20]. Moreover, mutations in CIITA predispose patients to immunological disorders, such as the bare lymphocyte syndrome [21]. All other NLR proteins contain a homotypic protein–protein interaction module at their N-terminus that enables them to recruit important signal transduction molecules after ligand sensing. These homotypic interaction modules are either a baculovirus inhibitor repeat domain (BIR), a caspase recruitment domain (CARD) or a pyrin domain (PYD), which define the subfamilies as NLRB, NLRC and NLRP, respectively (Fig. 1). Looking at the human NLRs, the NLRB subfamily contains one member, NAIP (BIRC3); the NLRC subfamily has six members, NOD1, NOD2, NLRC3, NLRC4 (IPAF), NLRC5 and NLRX1; and the NLRP subfamily has 14 members, NLRP1 to NLRP14 (Fig. 1). However, the NLRC subfamily appears to be more complex. NLRC3 and NLRC5 are likely to encode a homotypic interaction module belonging to the death-fold superfamily, though it has not been firmly established whether it is a CARD domain or another death-fold domain, death domain (DD), death effector domain (DED) or PYD. NLRX1 is included in the NLRC subfamily because it has a CARD-related ‘X’ domain [22]. Finally, the interaction module lacking CIITA contains a CARD-like domain in the isoform expressed in dendritic cells [23].

The importance of the NLR family to the innate immune system is further supported by the apparent evolutionary conservation of the NLR family. Indeed, to deal with pathogens and environmental insults, plant genomes contain many disease resistance genes, the so-called R genes, which encode a set of proteins containing nucleotide binding leucine-rich repeats (NB-LRR) [24].

Section snippets

Biological outcomes of procaspase-1 activity

Procaspase-1 is the founder member of an evolutionarily conserved family of cysteine-dependent aspartate-specific proteases named caspases, which are chiefly known for their involvement in the initiation and execution of apoptosis [25], [26]. However, procaspase-1 is not a pro-apoptotic protease. Instead, it plays an important role in innate immunity by processing and activating the pro-inflammatory cytokines IL-1β and IL-18, as well as by promoting an inflammatory type of cell death called

Role of NOD1 and NOD2 in health and disease

Initially, NOD1 (NLRC1) and NOD2 (NLRC2), two of the first characterized members of the NLR family, were reported to be intracellular sensors for LPS [262], [263], [264]. However, the LPS preparations used in those studies appeared to have been contaminated with other bacterial products. Subsequently, NOD1 and NOD2 were shown to recognize two different fragments of the bacterial cell wall component peptidoglycan: ieDAP (γ-d-glutamyl-meso-diaminopimelic acid) and MDP (MurNAc-L-Ala-d-isoGln),

Conclusions and perspectives

Since the discovery of the NLRP1 inflammasome and the NOD proteins a decade ago, a wealth of knowledge has been gained on the contribution of the NLR-family to innate immunity [59], [285], [286]. Of particular value are the elucidation of the underlying molecular mechanisms and the association of these proteins to an increasing number of pathologies, including gout, type II diabetes, atherosclerosis, silicosis, Alzheimer's disease, CD, CAPS, and a diverse range of infections. CAPS patients are

Kristof Kersse obtained his PhD in Biotechnology in 2011 at the Faculty of Sciences, Ghent University and the Flanders Institute for Biotechnology (VIB), Belgium. In his doctoral thesis he studied the role of the CARD domain of caspase-1 and the inflammasome complexes in the innate immune system. At the moment, he is a postdoctoral research fellow with Peter Vandenabeele at Ghent University and VIB, Belgium. His work focuses on the elucidation of the molecular mechanisms regulating

References (355)

  • J.G. Magalhaes et al.

    What is new with Nods?

    Curr Opin Immunol

    (2011)
  • K. Nickerson et al.

    Dendritic cell-specific MHC class II transactivator contains a caspase recruitment domain that confers potent transactivation activity

    J Biol Chem

    (2001)
  • S.M. Collier et al.

    NB-LRRs work a bait and switch on pathogens

    Trends Plant Sci

    (2009)
  • J.S. Matthews et al.

    Distinct roles for p42/p44 and p38 mitogen-activated protein kinases in the induction of IL-2 by IL-1

    Cytokine

    (1999)
  • T.D. Kanneganti et al.

    Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling

    Immunity

    (2007)
  • K. Nakanishi et al.

    Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu

    Cytokine Growth Factor Rev

    (2001)
  • C.E. Sutton et al.

    IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity

    Immunity

    (2009)
  • J. Schmitz et al.

    IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines

    Immunity

    (2005)
  • A.U. Lüthi et al.

    Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases

    Immunity

    (2009)
  • L. Agostini et al.

    NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle–Wells autoinflammatory disorder

    Immunity

    (2004)
  • F. Martinon et al.

    The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta

    Mol Cell

    (2002)
  • E. Elinav et al.

    NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis

    Cell

    (2011)
  • B. Faustin et al.

    Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation

    Mol Cell

    (2007)
  • J.L. Poyet et al.

    Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1

    J Biol Chem

    (2001)
  • Q. Bao et al.

    Calcium blocks formation of apoptosome by preventing nucleotide exchange in Apaf-1

    Mol Cell

    (2007)
  • S. Yuan et al.

    Structure of an apoptosome-procaspase-9 CARD complex

    Structure

    (2010)
  • D. Acehan et al.

    Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation

    Mol Cell

    (2002)
  • X. Jiang et al.

    Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to Apaf-1

    J Biol Chem

    (2000)
  • A.V. Diemand et al.

    Modeling AAA+ ring complexes from monomeric structures

    J Struct Biol

    (2006)
  • J. Masumoto et al.

    ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells

    J Biol Chem

    (1999)
  • S.M. Srinivasula et al.

    The PYRIN-CARD protein ASC is an activating adaptor for caspase-1

    J Biol Chem

    (2002)
  • J.S. Damiano et al.

    CLAN, a novel human CED-4-like gene

    Genomics

    (2001)
  • B.J. Geddes et al.

    Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis

    Biochem Biophys Res Commun

    (2001)
  • P. Broz et al.

    Differential requirement for caspase-1 autoproteolysis in pathogen-induced cell death and cytokine processing

    Cell Host Microbe

    (2010)
  • N. Kerur et al.

    IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi sarcoma-associated herpesvirus infection

    Cell Host Microbe

    (2011)
  • J.J. Chae et al.

    Gain-of-function pyrin mutations induce NLRP3 protein-independent interleukin-1beta activation and severe autoinflammation in mice

    Immunity

    (2011)
  • T.D. Kanneganti et al.

    Critical role for cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA

    J Biol Chem

    (2006)
  • F.S. Sutterwala et al.

    Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1

    Immunity

    (2006)
  • H. Kumar et al.

    Pathogen recognition in the innate immune response

    Biochem J

    (2009)
  • C. Huysamen et al.

    The fungal pattern recognition receptor, dectin-1, and the associated cluster of C-type lectin-like receptors

    FEMS Microbiol Lett

    (2009)
  • S. Vallabhapurapu et al.

    Function of NF-kB transcription factors in the immune system

    Annu Rev Immunol

    (2009)
  • A. Battistini

    Interferon regulatory factors in hematopoietic cell differentiation and immune regulation

    J Interferon Cytokine Res

    (2009)
  • T. Bergsbaken et al.

    Pyroptosis: host cell death and inflammation

    Nat Rev Microbiol

    (2009)
  • J.P.Y. Ting et al.

    How the noninflammasome NLRs function in the innate immune system

    Science

    (2010)
  • R. Cooney et al.

    Nod2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation

    Nat Med

    (2010)
  • L.H. Travassos et al.

    Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry

    Nat Immunol

    (2010)
  • J.A. Harton et al.

    Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains

    J Immunol

    (2002)
  • M. Krawczyk et al.

    Regulation of MHC class II expression, a unique regulatory system identified by the study of a primary immunodeficiency disease

    Tissue Antigens

    (2006)
  • W. Reith et al.

    THe bare lymphocyte syndrome and the regulation of MHC expression

    Annu Rev Immunol

    (2001)
  • A. Degterev et al.

    Expansion and evolution of cell death programmes

    Nat Rev Mol Cell Biol

    (2008)
  • Cited by (159)

    View all citing articles on Scopus

    Kristof Kersse obtained his PhD in Biotechnology in 2011 at the Faculty of Sciences, Ghent University and the Flanders Institute for Biotechnology (VIB), Belgium. In his doctoral thesis he studied the role of the CARD domain of caspase-1 and the inflammasome complexes in the innate immune system. At the moment, he is a postdoctoral research fellow with Peter Vandenabeele at Ghent University and VIB, Belgium. His work focuses on the elucidation of the molecular mechanisms regulating caspase-1-dependent pyroptosis in comparison with apoptotic and necrotic cell death.

    Mathieu JM Bertrand is Tenure Track member of the Faculty of Sciences, Ghent University, and postdoctoral researcher at the Flanders Institute for Biotechnology (VIB), Belgium. He obtained his PhD in Biomedical Sciences in 2005 at Namur University, Belgium. He did postdoctoral studies with Phil Barker at McGill University, Canada, and with Peter Vandenabeele at Ghent University and VIB, Belgium. His main research interests consist in the elucidation of the molecular mechanisms of non-degradative ubiquitination in cancer, cell death and inflammation. Now he focuses on these topics during ER stress.

    Mohamed Lamkanfi is member of the medical faculty at the Ghent University and the Flanders Institute for Biotechnology (VIB), Belgium. He obtained his PhD in Biochemistry in 2004 working on inflammatory caspases in the lab of Peter Vandenabeele at Ghent University and VIB. He did postdoctoral studies with Gabriel Nuñez at the University of Michigan, Ann Arbor, USA, and with Vishva Dixit at Genentech, San Francisco, California, USA. His group studies the role of NOD-like receptors and inflammasomes in immune signaling.

    Peter Vandenabeele is full professor at the Faculty of Sciences of the Ghent University, president of the Biochemistry and Biotechnology program at the Faculty of Sciences and group leader at the Flanders Institute for Biotechnology (VIB). He obtained his PhD in Biology at the Ghent University with Walter Fiers as promotor. He is an expert in cell death mechanisms, more precisely the role of caspases and RIP kinases.

    1

    These authors share senior authorship.

    View full text