Review

Correspondence *Academic Unit of Musculoskeletal Disease, Leeds Institute of Molecular Medicine (LIMM), University of Leeds, St James's University Hospital, Leeds LS9 7TF, UK

Email m.mcdermott@leeds.ac.uk

Introduction

The concept of innate immunity as the primitive cousin of the adaptive system, being nonspecific in most aspects of both recognition and response, has been transformed by the identification of the membrane-associated Toll-like receptors (TLRs) and the cytosol-expressed Nod-like receptors (NLRs).^{1, 2} Various levels of crosstalk between these two pathways have been described—most notably involving 'inflammasomes', intracellular multiprotein scaffold complexes that require input from both pathways. A series of discoveries involving a group of inherited chronic autoinflammatory disorders, the hereditary periodic fever syndromes, has helped to define the central roles of pyrin and NALP3 (NACHT domain, leucine-rich-repeat [LRR] domain, and pyrin domain [PYD]-containing protein 3; also known as cryopyrin, PYPAF1 [pyrin-containing Apaf1-like protein 1] and CIAS1 [cold-induced autoinflammatory syndrome 1]) in the genesis of inflammation. Characterization of both the NALP1 and NALP3 inflammasomes has provided remarkable insights into different mechanisms of innate immune responses and the regulation of one of the most important soluble mediators of inflammation, interleukin (IL)-1.

IL-1 is considered the prototypic 'multifunctional' cytokine, affecting nearly all cell types, either alone or in combination with other cytokines. Since its cloning in the early 1980s,³ investigation of the diverse biological activities of IL-1 has significantly increased our understanding of the pathogenesis of several diseases, including type 1 diabetes,⁴ gout,⁵ and many autoinflammatory disorders, including the NALP3-associated disorders (familial cold autoinflammatory syndrome [FCAS], Muckle–Wells syndrome [MWS], chronic infantile neurologic, cutaneous and articular syndrome/neonatal onset multisystem inflammatory disease [CINCA/NOMID]), in addition to pyogenic sterile arthritis with pyoderma gangrenosum and acne (PAPA).⁶ This Review will focus on inflammasomes—in particular, on the role of NALP3 in the regulation of IL-1 production and the potential implications of IL-1 dysregulation in the pathogenesis of several of these disorders.

Toll-like receptors and NOD-like receptors

Innate immunity provides a rapid means of host defense by responding to microbial 'pattern' molecules, such as cell-wall products (e.g. peptidoglycan). Recognition occurs through a variety of germline-encoded pattern receptor molecules (PRMs), such as TLR family members, which sense extracellular ligands. Recognition triggers a series of events that leads to the expression of many immune and inflammatory genes. To date, a total of 10 TLRs (TLR1–10) in humans and 12 TLRs (TLR1–9 and TLR11–13) in mice have been described.⁷ These are homologs of the prototype Toll molecule, which was originally identified in Drosophila melanogaster, and are arguably the most studied of the PRMs.^{8, 9} Endogenous cellular products associated with tissue injury or self 'danger' signals, such as toxic compounds, defective nucleic acids, or the presence of normal cell components in atypical extracellular or intracellular locations, can also stimulate innate immune mechanisms through NLRs.^{10, 11} The NLR family of PRMs includes 22 members in humans. The NLRs are the cytoplasmic counterparts of TLRs and sense microbial patterns that gain access to the cell, in addition to various metabolic stresses. Nucleotide-binding oligomerization domain (NOD) 1 and NOD2 were the first NLRs reported to function as intracellular sensors, recognizing distinct substructures of bacterial peptidoglycan. The NLR family broadly encompasses 5 members of the NOD subfamily, 14 NALPs, IPAF (IL-1-converting enzyme [ICE]-protease-activating factor), NAIPs (neuronal apoptosis inhibitor factors), and CIITA (major histocompatibility complex [MHC] class II transactivator).¹² The basic structural features and immunology of the NLR system have been reviewed in detail.^{13, 14} Briefly, NLRs are characterized by three domains: an N-terminal effector domain, which can be a PYD, a caspase-recruitment domain (CARD), or a baculovirus inhibitor of apoptosis protein repeat (BIR);¹ an intermediary nucleotide-binding domain (NBD; NACHT or NAD); and a C-terminal LRR domain (Figure 1).

Figure 1 Domain structure of several Nod-like receptors (NLRs).

For comparison, the structure and domains of seven of the more prominent NLR family members are shown. The CARD domain depicted in CIITA is only present in some splice forms; the majority of transcripts encoding CIITA do not have a CARD. Abbreviations: AD, activation domain; BIR, baculovirus IAP (inhibitor of apoptosis protein) repeat; CARD, caspase-recruitment domain; CIITA, major histocompatibility complex (MHC) class II transactivator; FIIND, domain with function to find; IPAF, interleukin 1-converting enzyme protease-activating factor; LRR, leucine-rich repeat; NACHT, domain present in NAIP, CIITA, HET-E (incompatibility locus protein from Podospora anserine) and telomerase-associated protein; NAD, NACHT-associated domain; NAIP, neuronal apoptosis inhibitor protein; NALP, NACHT domain, LRR domain, and pyrin domain-containing protein; PYD, pyrin domain.

Full figure and legend (37K)Figures & Tables indexDownload Power Point slide (110K)

The ligands and functions of many of these NLRs are still being identified (Supplementary Table 1 online); NOD2 recognizes muramyl dipeptide, a molecular motif released from peptidoglycan that is common to Gram-negative and Gram-positive bacteria.¹⁵ NOD2 mutations have been identified as determinants of genetic susceptibility to Crohn's disease, but the pathogenic role of these mutations remains unclear.^{16, 17} Mutations in the NACHT domain of NOD2 also underlie susceptibility to Blau syndrome, an autosomal-dominant condition comprising granulomatous arthritis, iritis, and skin rash.^{18, 19} These mutations are thought to lead to excessive downstream basal activity of the transcription factor nuclear factor B.²⁰ Interestingly, the three residues in the NACHT domain of NOD2 affected by mutations in Blau syndrome correspond to the same positions of pathogenic mutations in the NACHT domain of the closely related NALP3 protein that cause susceptibility to CINCA/NOMID, FCAS, and MWS.²⁰ More recently, NOD2 mutations have also been implicated in early-onset sarcoidosis, a disease with similar clinical features to Blau syndrome.²¹

Much intracellular crosstalk occurs between TLRs and NLRs, which might lead to the generation of pro-IL-1 and other inflammatory cytokines, including IL-18 and IL-33.^{22, 23, 24} For instance, TLR ligands, such as lipopolysaccharide, induce activation of nuclear factor B, thereby triggering gene expression and synthesis of pro-IL-1. Conversion of pro-IL-1 to its active form requires not only activation of caspase 1 (also known as IL-1-converting enzyme),²⁵ but also a second stimulus to induce the formation of the inflammasome, to enhance the proteolytic maturation and secretion of IL-1.¹⁴

NALPs

NALPs form the largest family of PYD-containing proteins; the human genome contains 14 NALP genes (NLRP [NLR family, pyrin-domain-containing] is the Human Genome Organization [HUGO] Gene Nomenclature Committee approved nomenclature for NALP genes but, because this topic is currently one of active discussion, the NALP nomenclature in current use is used here). Genomic analysis implies that these genes have evolved through duplication events. Several NALP genes, such as NALP2, NALP4, and NALP7 in humans, are apparent paralogs of mouse loci.

As outlined above, NALPs comprise an N-terminal PYD domain, a NACHT domain, and a variable number of LRRs (Figure 1). LRRs are short repeat motifs (22–28 residues) that are found in a variety of cytoplasmic, membrane, and extracellular proteins, including TLRs and plant resistance proteins, both of which sense pathogens via this domain. Although NALPs have a wide range of functions, most seem to be involved in protein–protein interactions.

The inflammasomes

Inflammasomes are multiprotein cytoplasmic complexes that mediate the activation of inflammatory caspases: caspase 1 can be activated by both the NALP1 and NALP3 inflammasomes, whereas only the NALP1 inflammasome activates caspase 5. Caspase 1 cleaves pro-IL-1 to IL-1 and also activates IL-18 and IL-33; in this manner, the enzyme controls the maturation of some of the proinflammatory cytokines. The NALP1 inflammasome, which was the first molecular platform to be described, is a large intracellular complex composed of caspase 1, caspase 5, NALP1, and an adaptor known as apoptosis-associated speck-like protein containing a CARD (ASC).²⁶ However, several other inflammasomes have subsequently been identified.

The NALP3 inflammasome

NALP3, which is probably the best understood of the different NALPs, is involved in the recognition of numerous exogenous and host ligands.²⁷ The different components of the NALP3 inflammasome include NALP3 itself, CARDINAL (which is thought to be a functional homolog of the C-terminus of NALP1), ASC, and caspase 1.²⁸ After being processed by caspase 1, IL-1 is secreted together with the active caspase 1 molecule (Figure 2).^{29, 30}

Figure 2 Activation of the NALP3 inflammasome.

Engagement of specific TLRs leads to activation of NFB signaling pathways, inducing the expression of pro-IL-1 or pro-IL-18. NALP3 is the central component of the NALP3 inflammasome; in its inactive state the LRR domain of NALP3 is thought to self-associate, preventing interaction with CARDINAL or ASC. NALP3 activation by agonists, such as ATP, MDP, uric acid crystals, bacterial messenger RNA, or skin irritants, unfolds the NALP3 molecule, enabling the assembly of the inflammasome components CARDINAL, ASC, and procaspase 1 through homotypic interactions between their respective pyrin (PYD) and CARD domains; CARDINAL interacts with the NAD domain of NALP3 through its FIIND domain. The oligomerization of inflammasome complexes induces cleavage of procaspase 1 to its active form, resulting in the generation of active IL-1 from its inactive precursor pro-IL-1. VX-765 is a potent, selective, competitive inhibitor of caspase 1; COP, Iceberg, and PI9 can interfere with caspase activation. Several molecules (IL-1Ra, IRAP, and IL-1 mAbs) inhibit IL-1 activity. Abbreviations: ASC, apoptosis-associated speck-like protein containing a CARD; CARD, caspase-recruitment domain; COP, CARD-only protein; FIIND, domain with function to find; IL, interleukin; IL-1Ra, IL-1 receptor antagonist; IRAP, IL-1 receptor accessory protein; LRR, leucine-rich repeat; mAb, monoclonal antibody; MDP, muramyl dipeptide; MSU, monosodium urate; NACHT, domain present in neuronal apoptosis inhibitor protein (NAIP), major histocompatibility complex class II transactivator, HET-E (incompatibility locus protein from Podospora anserina) and telomerase-associated protein; NAD, NACHT-associated domain; NALP, NACHT domain, LRR domain, and pyrin domain-containing protein; NFB, nuclear factor B; PI9, proteinase inhibitor 9; PYD, pyrin domain; TLR, Toll-like receptor.

Full figure and legend (49K)Figures & Tables indexDownload Power Point slide (122K)

The mechanisms of activation of the NALP3 inflammasome are gradually being deciphered; it recognizes a range of compounds, including bacterial RNA, ATP, and uric acid crystals (hence the acute inflammation observed in gout), and the antiviral imidazoquinoline compounds R837 and R848.^{31, 32} NALP3 activation is also triggered by low concentrations of intracellular potassium³³ and by UVB ultraviolet light;³⁴ sensing of these stimuli causes NALP3 to oligomerize, recruit ASC and caspase 1, and form an active inflammasome complex (Figure 2).^{35, 36}

Inflammasome activity can be dampened down by a variety of cytoplasmic proteins, including pyrin,³⁷ a protein associated with susceptibility to familial Mediterranean fever (FMF).³⁸ Recently, NALP3 has been proposed to be involved in the sensitization phase of contact-hypersensitivity allergic responses. Mice that lack either ASC or NALP3 have impaired contact-hypersensitivity responses to skin irritants, such as trinitrophenylchloride, 2,4,6,-trinitrochlorobenzene, and 2,4-dinitrofluorobenzene.^{39, 40} Dinitrofluorobenzene can trigger the release of IL-1 in keratinocytes and dendritic cells, which implies that these irritants might directly activate NALP3.³⁹ These findings demonstrate an involvement of the NALP3 inflammasome in the T-cell-dependent contact-hypersensitivity response and provide further support for a role of NLRs in linking innate and adaptive immune responses.

Interleukin 1

One of the main functions of IL-1 is as a pyrogenic cytokine, produced mainly by blood monocytes. IL-1 is normally produced in response to infection, injury, or immunologic challenge;²⁸ at minimal concentrations, it causes fever, hypotension, and production of additional proinflammatory cytokines, such as IL-6. The IL-1 family has expanded from the three founding members (IL-1, IL-1, and the IL-1 receptor antagonist [IL-1Ra]) to include IL-18, IL-33, and five other members (on the basis of amino acid sequence conservation and identity of either the gene or the three-dimensional structure).^{22, 23, 24, 41} The synthesis and release of IL-1 is very tightly regulated (unlike that of other cytokines, such as tumor necrosis factor);²⁸ the immune system has evolved several mechanisms to regulate excessive production or dysregulation of IL-1, from transcription of the IL1B gene to cleavage of the 35 kDa pro-IL-1 precursor to generate the mature 17 kDa product.⁴² Several proteins—in particular, some CARD-containing proteins, such as the CARD-only protein (COP), Iceberg, the caspase 1 inhibitor proteinase inhibitor 9 (PI-9), and pyrin—are believed to regulate IL-1 production by interfering with the recruitment of caspase 1 or directly neutralizing caspase 1 activity.^{43, 44, 45} Other putative negative regulators of inflammasome activity have been described, such as pyrin-only protein 1 (POP1; also known as ASC2) and POP2.^{46, 47} Much current research is devoted to understanding the mechanisms of action of these molecules, considering their potential as therapeutic agents.

Inflammatory disorders and inflammasomes

A growing number of systemic inflammatory diseases, characterized by fever, anemia, and elevated levels of acute-phase proteins, have been linked to excessive production and bioactivity of IL-1; all these conditions respond, to varying degrees, to specific blockade of the IL-1R.⁴⁸ Furthermore, several of these disorders are associated with abnormalities in NLR signaling pathways, as exemplified by the 'cryopyrinopathies', which are also termed 'the CIAS1-associated periodic syndromes'.

Conclusions

Inflammasomes and IL-1 are involved in the pathogenesis of several inflammatory disorders. The remarkable progress in this field has offered new hope for many patients with these disorders and also highlighted the role IL-1 might have in other inflammatory disorders, such as sJIA, AOSD, and rheumatoid arthritis (RA). The efficacy and efficiency of IL-1 blockade with anakinra in patients with MWS, FCAS, and CINCA/NOMID are countered by its short half-life (requiring daily subcutaneous injections) and diurnal variation in concentration. However, anakinra is a proof-of-principle for IL-1 blockade in these disorders, and a new generation of IL-1 antagonists can be anticipated in the near future. The development of antagonists with higher affinities and longer half-lives will facilitate patient management and also assist patient compliance. It will also be necessary to determine whether disruption by anakinra of the vicious circle of IL-1 production induced by IL-1 is the major cause of decreased secretion of this cytokine following treatment or whether some other mechanism is involved.

The new generation of compounds that has been developed includes a long-acting fully humanized IL-1 antibody, a soluble IRAP, and IL-1 Trap (a combination of IL-1R type I and IRAP). An IL-1 monoclonal antibody is currently in phase II trials for both MWS and RA, and IL-1 Trap has received orphan drug designation by the US FDA for the treatment of cryopyrinopathies. A gene-therapy approach is also being developed to deliver IL-1 inhibitors. In a phase I clinical trial of nine postmenopausal women affected by treatment-resistant RA, synoviocytes were transduced ex vivo with a recombinant retrovirus expressing an IL-1Ra and reinjected into multiple joints.⁷⁶ The gene was expressed in all joints that received the transgene, and the procedure was well tolerated by the patients. However, this regimen is currently too complex for routine use and the levels of IL-1Ra expression in vivo were not sufficiently high to ensure long-term anti-inflammatory levels.

In addition to these specific IL-1-targeting agents, the development of caspase 1 inhibitors has shown encouraging results. In studies using the orally available prodrug VX-765, a potent, selective, competitive inhibitor of caspase 1, IL-1 secretion was blocked in lipopolysaccharide-stimulated peripheral blood mononuclear cells from FCAS patients and control subjects.⁷⁷ VX-765 also reduced disease severity in a collagen-induced arthritis mouse model.⁷⁸

Despite the increasing evidence for the involvement of IL-1 in tissue destruction and disease persistence in RA, and the benefit of blocking this pathway in animal models of RA, anakinra has provided little therapeutic benefit to RA patients. IL-1 is an extremely potent cytokine and must, therefore, be blocked continuously, which might explain, in part, the limited efficacy of anakinra in RA. In systemic autoinflammatory disorders, anakinra has direct 'access' to its IL-1 target in the blood; this is not the case in RA, in which the deleterious effects of IL-1 are mediated primarily in the joints. Constitutively blocking cytokines might interfere with the efficiency of the immune system to cope with infection. This difficulty has been most publicized with the use of antitumor necrosis factor therapies and consequent increase in rates of Mycobacterium tuberculosis infection. To date, few opportunistic infections have been reported with the long-term use of anakinra, although the first case of tuberculosis reactivation in an RA patient treated with anakinra has recently been reported.⁷⁹ The results of clinical trials of other IL-1 inhibitors will, therefore, provide valuable information on the use of IL-1 inhibition in the treatment of RA and other rheumatic diseases.

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