Originally published online as doi:10.1189/jlb.1003473 on December 12, 2003
Published online before print December 12, 2003
(Journal of Leukocyte Biology. 2004;75:738-742.)
© 2004
by Society for Leukocyte Biology
Extracellular and intracellular decoys in the tuning of inflammatory cytokines and Toll-like receptors: the new entry TIR8/SIGIRR
Alberto Mantovani*,
,1,
Massimo Locati,
Nadia Polentarutti*,
Annunciata Vecchi* and
Cecilia Garlanda*
* Department of Immunology and Cell Biology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy; and
Centro di Eccellenza per l'Innovazione Diagnostica e Terapeutica (IDET) Institute of General Pathology, Faculty of Medicine, University of Milan, Italy
1 Correspondence: Department of Immunology and Cell Biology, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy. E-mail: Mantovani{at}marionegri.it
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ABSTRACT
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Following the identification of the interleukin (IL)-1 type II receptor as a prototypic decoy receptor, nonsignaling receptors with decoy functions have been identified for members of the IL-1/IL-18, tumor necrosis factor, IL-10, and IL-13 receptor families. Moreover, the silent receptor D6 is a promiscuous decoy and scavenger receptor of inflammatory chemokines. The type II IL-1 decoy receptor also acts as a dominant-negative molecule. Intracellular pathways of inhibition of IL-1 and Toll-like receptor (TLR) signaling have been identified. In particular, recent results suggest that the Toll/IL-1 receptor (TIR) family member TIR8, also known as single immunoglobulin IL-1-related receptor (SIGIRR), is a negative regulator of IL-1 and TLR signaling. Thus, extracellular and intracellular decoys tune the activation of members of the IL-1/TLR receptor family.
Key Words: inflammation • interleukin-1 • signaling • chemokines
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INTRODUCTION
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Tuning of the action of inflammatory cytokines plays a key role in innate immunity and inflammation. Interleukin (IL)-1 is a prototypic inflammatory cytokine, which has served as a paradigm for the definition of signaling and regulatory systems [1
]. The action of IL-1 is regulated at multiple levels, extracellularly and intracellularly (Fig. 1
). The IL-1ra represents a classic, negative pathway of regulation [2
]. Released and intracellular isoforms of IL-1ra have been identified. It is, at present, unclear whether icIL-1ra is only a depot of this anti-inflammatory molecule or exerts intracellular inhibitory functions [3
]. The type II IL-1 decoy receptor (IL-1RII) represents a second negative pathway of regulation of IL-1 [4
, 5
]. Here, we will concisely review recent progress in the definition of the mode of action and function of the IL-1 decoy RII. Moreover, intracellular pathways of negative regulation of IL-1, including decoys that trap components of the signal-transduction machinery, will be discussed, with emphasis on the single Ig domain receptor TIR8, also known as SIGIRR. Tir8 was originally used when the mouse gene sequence was deposited by this group in 1998 (accession no. AF113795; for the SIGIRR nomenclature, see ref. [6
]). Finally, evidence showing that decoy receptors represent a general strategy to tune the action of inflammatory cytokines and chemokines will be summarized.
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Figure 1. Negative pathways of regulation of IL-1 receptor (R) and Toll-like receptor (TLR) signaling. LPS, Lipopolysaccharide; AcP, accessory protein; SIGIRR, single immunoglobulin (Ig) IL-1-related receptor; TIR8, Toll/IL-1 receptor-8; IRAK, IL-1R-associated kinase; TRAF, tumor necrosis factor (TNF) receptor-associated factor; MAL, MyD88-adapter-like; TIRAP, Toll/IL-1R domain-containing adapter protein; TRIF, Toll/IL-1R domain-containing adapter-inducing interferon (IFN)-ß; TOLLIP, Toll-interacting protein; SOCS, suppressor of cytokine signaling; JNK, c-jun NH2-terminal kinase; NF- B, nuclear factor-B; sIL-1ra, soluble IL-1R antagonist; icIL-1ra, intracellular IL-1ra.
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THE IL-1 TYPE II DECOY RECEPTOR AS A PARADIGM
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Several lines of evidence are consistent with the view that the IL-1RII is a pure decoy for IL-1 [4
, 5
, 7
]. The original proposal of the decoy paradigm was based on blocking antibodies to IL-1RII, which amplified responsiveness of myelomonocytic cells to IL-1, as well as on stimulation of expression by anti-inflammatory agents (see below) [4
, 7
8
9
]. These observations have been confirmed and extended in vivo. Gene transfer experiments have shown that IL-1RII gene transfer blocks in vitro cellular responses to IL-1 in diverse cellular contexts [9
10
11
]. Moreover, transfer of IL-1RII transfected cells ameliorates collagen-induced arthritis in mice [12
]. In addition to binding IL-1, the IL-1RII forms a complex with the agonist and the IL-1R AcP. Therefore, it acts as a dominant-negative for the formation of a signaling receptor complex by sequestering AcP, essential for signal transduction [13
, 14
]. In summary, IL-1RII blocks IL-1 in vitro and in vivo in two complementary ways. First, in membrane-bound [11
] or soluble form, it acts as a decoy, capturing IL-1ß and preventing its interaction with IL-1RI. Moreover, in concert with soluble AcP, it also binds and blocks IL-1
[15
]. Second, it acts as a dominant-negative molecule for signaling receptor complexes. Finally, recent data suggest that in neutrophils, the decoy receptor also acts as a scavenger [16
] (Fig. 1)
. At least certain pro- and anti-inflammatory signals have divergent effects on IL-1RII expression and release in myelomonocytic cells, with inhibition, for instance, by IFN-
and stimulation by IL-4 and glucocorticoids (GC). The IL-1RII balance is a component in setting myelomonocytic cells in a pro- or anti-inflammatory mode [5
].
Alterations of tissue or body-fluid levels of IL-1RII have been detected in diverse pathological conditions. Increased blood levels of IL-1RII have been detected in experimental endotoxemia, sepsis, acute meningococcal infection, and in patiens treated with IL-2, aspirin, or GC [17
18
19
20
21
22
23
]. Recent results suggest that levels of IL-1RII may serve as a readout of the activation of endogenous, anti-inflammatory pathways, for instance, by GC hormones [24
, 25
].
Joint inflammation has been extensively investigated and could represent a target for IL-1RII-based therapeutic strategies. sIL-1RII was present in inflammatory synovial fluids [26
, 27
]. Gene array analysis of osteoarthritis lesions showed a lack of expression of IL-1RII and IL-1ra [27
]. Overexpression of IL-1RII in chondrocytes protected them from IL-1 stimulation [27
]. Moreover, transfer of cells transfected with IL-1RII, which overexpress and relase this molecule, resulted in inhibiton of collagen arthritis [12
].
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INTRACELLULAR INHIBITORS OF IL-1R AND TLR SIGNALING: TIR8
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Inhibitors of signaling also intracellulary regulate cellular activation by members of the IL-1R/TLR receptor family. These include the member of the IRAK family IRAK-M, a spliced version of MyD88 and SOCS1 [28
29
30
]. Recent evidence suggests that the IL-1R family member TIR8 (also known as SIGIRR) is an intracellular inhibitor of IL-1R/TLR signaling (Fig. 1)
. TIR8 has a unique pattern of expression, with low levels in macrophages and endothelial cells and high mRNA levels in epithelial organs such as kidney and gut [31
, 32
].
Pro- and anti-inflammatory signals generally do not affect TIR8 expression, but LPS down-regulates it in vitro and in vivo. It is interesting that other orphan members of the IL-1R family such as T1/ST2 are up-regulated by LPS [33
]. TIR8 gene transfer experiments have revealed that it reduces NF-B activation by the IL-1R complex [32
], as well as by members of the TLR family such as TLR4 [31
]. Recruitment of TIR8 at IL-1R/TLR signaling receptor complexes sequesters key signaling elements such as TRAF6 and IRAK (Fig. 1)
.
TIR8/SIGIRR-deficient mice have been generated (ref. [31
] and our unpublished data). TIR8 deficiency was associated with increased susceptibility to LPS toxicity [31
] or to a selective increase in susceptibility to mucosal inflammation (C. Garlanda et al., unpublished data). Thus, available information in vitro and in vivo is consistent with the hypothesis that TIR8 negatively regulates IL-1R/TLR signaling by acting as a decoy for key components of the signaling cascade.
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CYTOKINE DECOY RECEPTORS FOR OTHER INFLAMMATORY CYTOKINES AND CHEMOKINES
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IL-18 is a member of the IL-1 family. By chromatography on IL-18, Novick et al. [34
] isolated an IL-18-binding protein (IL-18BP), which is an Ig superfamily-related receptor, expressed in multiple isoforms, capturing IL-18 and blocking its activity. IL-18 is a soluble protein, which contains a single putative Ig domain. The IL-18BP Ig domain bears some homology to the third Ig domain of the IL-1RII. IL-18BP shows considerable homology to a family of proteins (p13/p16) encoded by poxviruses, and one of these (Ectormelia p13) has been demonstrated to bind and inactivate IL-18 [35
].
Various decoy receptors have been identified in the TNF receptor superfamily [36
]. A trio of agonist, receptor, and decoy receptor orchestrates bone resorption by regulating the development and activation of osteoclasts. Receptor activator of NF-B ligand (RANK) is a member of the TNF receptor family [37
, 38
]. It interacts with RANK ligand [or osteoprotegerin ligand (OPGL) or TNF-related, activation-induced cytokine], a TNF superfamily member that acts as a trimer. OPG, protector of bone or osteoclastogenesis-inhibitory factor, is a secreted TNF receptor family member that binds OPGL and blocks its activity. Genetic (including gene-targeting) and functional studies in vitro and in vivo indicate that OPG is a pure, soluble decoy receptor [39
40
41
42
43
]. OPG also binds and neutralizes TNF--related apoptosis-inducing ligand (TRAIL) [36
, 37
]. Two decoy receptors for TRAIL have been described, DcR1 and DcR2 [38
, 44
]. DcR1 is a glycosylphosphatidylinositol-anchored cell-surface protein, whereas DcR2 is a transmembrane protein with a truncated death domain. Decoy receptors modulate the sensitivity of normal and neoplastic cells to TRAIL cytotoxicity. Regulation of TRAIL toxicity could be crucial to exploit its antitumor activity given its cytotoxicity for normal human hepatic epithelial cells [45
, 46
].
Susceptibility of Fas-expressing cells to apoptosis can be regulated at different levels, including decoy receptors. Alternative splicing of Fas yields soluble forms, which could potentially block Fas ligand (FasL). In addition, alternative splicing of exon 7 results in a membrane-bound Fas isoform [Fas decoy receptor (FDR)], which lacks the death domain [47
]. FDR is expressed in thymocytes and blocks apoptosis by forming mixed receptor trimer complexes incapable of triggering death [48
]. DcR3 (or TR6) is a soluble Fas decoy receptor encoded by a separate gene [48
, 49
]. It lacks a transmembrane region and is secreted by cells. DcR3 binds FasL and LIGHT [49
].
A soluble decoy receptor has been identified for IL-22, a member of the IL-10 family [50
, 51
]. Moreover, the IL-13R2 chain has been suggested to act as decoy receptor for IL-13, based on a variety of criteria including gene targeting [52
, 53
].
The identification of functional decoy receptors for chemokines [54
] prompted us to search for chemokine "receptors" structurally incapable of signaling. We focused our attention on chemokine receptors (or putative chemokine receptors), which have modified sequence motifs (a D residue in the second transmembrane domain and a DRY motif in the second intracellular loop), known to be essential for signaling. In particular, D6 is a promiscuous chemokine-binding molecule with a restricted pattern of expression, which includes placenta and lymphatic endothelial cells [55
]. We first observed in diverse cellular contexts that binding of the inflammatory chemokine CCL2 is followed by rapid internalization and degradation of the ligand [56
]. Under no experimental conditions did we find evidence that D6 facilitated tranfer (transcytosis) of chemokines across lymphatic endothelium in the apical-to-basal or basal-to-apical direction. We have recently analyzed more in-depth the spectrum of ligands recognized by D6, including N-terminal processed chemokines. We found that D6 binds and scavenges most inflammatory chemokine agonists at CCR1 through CCR5. Conversely, homeostatic chemokine agonists at CCR6 and CCR7 are not recognized. These results indicate that the silent, promiscuous receptor D6 acts as a structural decoy receptor and scavenger for inflammatory chemokines (R. Bonecchi, unpublished data) and together with the restricted expression of D6 on endothelial cells lining afferent lymphatics [55
], suggest that D6 may act as a gatekeeper to prevent excessive transfer of inflammatory chemokines to lymph nodes (ref. [56
] and R. Bonecchi, unpublished data).
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ACKNOWLEDGEMENTS
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This work was supported by EC, Instituto Superior di Sanità, MIUR (projects FIRB RBNE01Y3N3 and RBNE01W9PM), Ministero della Salute and AIRC.
Received October 10, 2003;
accepted October 22, 2003.
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ABSTRACT
INTRODUCTION
