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Commentary

Gout: new insights into an old disease

Fabio Martinon1 and Laurie H. Glimcher1,2

1Department of Immunology and Infectious Diseases, Harvard School of Public Health, and 2Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Address correspondence to: Laurie H. Glimcher, 651 Huntington Avenue, Building FXB Room 205, Boston, Massachusetts 02115, USA. Phone: (617) 432-4846; Fax: (617) 432-0084; E-mail: lglimche@hsph.harvard.edu .

Published August 1, 2006

Gout is an autoinflammatory disorder associated with deposition of monosodium urate (MSU) crystals in joints and periarticular tissues. Recent advances suggest that the innate immune system may drive the gouty inflammatory response to MSU. These findings prompt questions concerning how the innate immune system recognizes MSU and the identities of the receptors involved. In this issue of the JCI, Chen et al. show that the IL-1 receptor and its signaling protein myeloid differentiation primary response protein 88 (MyD88) but not the “classical” innate immune receptors, TLRs, are central for MSU-induced inflammation (see the related article beginning on page 2262).

See the related article beginning on page 2262.

MSU in gout: a role for the innate immune system?

Gout is considered one of the most painful acute conditions that human beings can experience and was among the first diseases recognized as a distinct entity. Through the ages, gout has captured the attention of many famous physicians, including the Egyptian Imhotep, who lived in the 27th century BCE, and the revered Hippocrates (ca. 460–377 BCE), who made the distinction between gout (Greek: podagra) and other forms of arthritis (1). Gout is generally associated with hyperuricemia and is characterized by deposition of monosodium urate (MSU) crystals within the joints (2). Back in the 1960s, Faires and MacCarty, in a heroic effort to study the role of MSU crystals in gout, injected their left knee joints with 20 mg of MSU crystals. Both rapidly developed an acute inflammation displaying all the characteristics of violent gouty attacks, that left them, 4 hours after injection, prostrate with excruciating pain. After recovering, they reported: “At this point we were impressed by the accuracy of Sydenham’s [1683] classic description of gout” (3). Their experiment clearly demonstrated that MSU crystals are the initial trigger of gout and prompted the fundamental question as to how MSU crystals activate the immune system to drive inflammation. A recent breakthrough by Kenneth Rock’s laboratory demonstrated that uric acid released from “damaged cells” forms MSU crystals, which act as a “danger signal” capable of maturing dendritic cells, driving antigen presentation and stimulating T lymphocytes (4). This finding was very exciting for two main reasons. First, it suggested a function for MSU crystals, beyond their role in gout, in facilitating an efficient immune response, as might occur in the course of tissue damage associated with infection (5). Second, Rock’s observation revealed that the type of dendritic cell response elicited by MSU crystals strongly resembled the response elicited by exogenous adjuvants, a class of molecules that stimulate the innate immune system to promote antigen presentation and stimulate T cell responses (6). These observations were therefore consistent with the hypothesis that MSU crystals directly activate the innate immune system.

Role of the TLRs

In this issue of the JCI, a new study from Rock’s laboratory, by Chen et al., investigates the role of various components of the innate immune system in MSU-mediated inflammation (7). TLRs are the best characterized family of innate immune receptors. These transmembrane proteins sense structural components shared by many microbes and are particularly adept in activating dendritic cells, a crucial step that links the innate and adaptive immune responses (8). To investigate the role of TLRs, Chen et al. injected MSU crystals into the peritoneal cavity of either wild-type mice or mice deficient in various TLRs and monitored inflammation by quantifying neutrophil influx. Strikingly, none of the 9 TLR-deficient mouse strains analyzed showed an impairment in neutrophil influx, suggesting that TLRs may not be crucial for MSU-induced inflammation. To confirm these findings and rule out a possible role for TLR5 or TLR8 (since mice deficient in these TLRs are not available), the authors reconstituted a cell line with all the TLRs and monitored the ability of MSU crystals to activate these receptors. None of the 11 TLRs tested responded per se to stimulation by MSU crystals (7). Although these negative results do not rule out the possibility that an unidentified coreceptor may cooperate with a TLR to recognize MSU, taken together with the results of the knockout mice studies, they render the hypothesis that TLRs sense MSU unlikely.

IL-1β and the IL-1 receptor: key players in MSU crystal–mediated inflammation

A key structural motif involved in TLR signaling is the Toll/IL-1 receptor (TIR) domain. TIR can be found in the cytoplasmic portion of all TLRs, members of the IL-1 receptor (IL-1R) family, and a group of adaptor proteins including myeloid differentiation primary response protein 88 (MyD88), TIR domain–containing adaptor protein (TIRAP), TIR domain–containing adaptor–inducing IFN-β (TRIF), and TRIF-related adaptor molecule (TRAM), all of which play fundamental roles in TLR and IL-1R signaling (9). When Chen et al. analyzed mice deficient in these adaptors, MSU crystal–induced inflammation was not impaired in TIRAP-, TRIF-, and TRAM-deficient mice but, surprisingly, was almost completely abolished by MyD88 deficiency (7). This prompted the authors to investigate the role of the IL-1Rs, the other receptor family that signals via MyD88, and led to the provocative observation that MSU crystal–induced inflammation requires IL-1R. This result was unexpected, considering that IL-1R is generally not believed to be an innate immune receptor, but makes sense in light of recent insights into the mechanism that controls the activation of the IL-1R ligand IL-1β. IL-1β is a proinflammatory cytokine whose production and activation involve 3 main steps: first, the production of the precursor pro–IL-1β; second, the maturation of the precursor; and finally the secretion of the mature IL-1β into the extracellular space. The maturation is a very specific step that requires the activation of a protease, caspase-1, by a member of the NOD-like receptor (NLR) family. NLRs are intracellular receptors that detect microbes and constitute an emerging branch of the innate immune system (10). Some NLRs, such as NACHT, LRR, and pyrin domain–containing protein (NALP), neuronal apoptosis inhibitory protein (NAIP), and ICE protease–activating factor (IPAF), form complexes called inflammasomes that are involved in the activation of caspase-1. Interestingly, MSU crystals were recently shown to activate NALP3, and macrophages deficient in various components of the NALP3 inflammasome are unable to secrete active IL-1β following MSU crystal stimulation (11). This finding is consistent with the concept that IL-1β induced by MSU crystals may then trigger inflammation through an IL-1R/MyD88–dependent pathway. Furthermore, using bone marrow chimera experiments, Chen et al. show that MSU crystal–mediated inflammation does not require IL-1R and MyD88 in bone marrow cells, suggesting that other cell types respond to IL-1β to transmit the inflammatory signal (7).

Conclusion

Based on these recent findings, gouty inflammation can be divided into two phases (Figure 1). The first phase (IL-1β maturation) requires phagocytic cells such as monocytes to internalize MSU crystals and activate the NALP3 inflammasome to alert the surrounding environment via the processing and release of active IL-1β (11). This step probably does not involve MyD88 or TLRs, although we cannot exclude a possible role for the TLRs in promoting IL-1β precursor synthesis or crystal phagocytosis (12). The second phase (IL-1β elicitation) corresponds to an inflammatory response driven by IL-1R and MyD88 activation in non–bone marrow–derived cells resulting in the production of chemokines and inflammatory mediators that elicit neutrophil influx to the joints, characteristic of gouty inflammation (7). Although the results discussed here are essentially based on a mouse model of MSU crystal–induced inflammation, they suggest a general model of the mechanism of gouty inflammation that raises a host of new questions. For instance, it is not clear what cell types respond to IL-1β in the joints. We might anticipate that synoviocytes or endothelial cells play a central role in recruiting neutrophils (13, 14), but other cell types may be affected. For example, IL-1β may promote osteoclast activation and differentiation and trigger inflammatory pain hypersensitivity by acting on neurons (15).

Model of the role of IL-1β in gouty inflammation.Figure 1

Model of the role of IL-1β in gouty inflammation. MSU crystals internalized by monocytes activate the NALP3 inflammasome (Phase 1, lower left). NALP3 protein activation leads to the recruitment and activation of the adaptor ASC and caspase-1 via PYD-PYD and CARD-CARD homotypic interactions, resulting in the processing and maturation of pro–IL-1β into its biologically active form, IL-1β. IL-1β (mainly acting on nonleukocytic cell types, possibly synoviocytes) will then activate the IL-1R complex, leading to recruitment of MyD88 via TIR-TIR homotypic interactions. This results in the activation of NF-κB, which will turn on the transcription of neutrophil-recruiting chemokines, such as IL-8, S100, or macrophage inflammatory protein 2 (MIP-2) (Phase 2, lower right). ASC, apoptosis-associated speck-like protein containing a CARD; CARD, caspase-recruitment domain; DD, death domain; PYD, pyrin domain.

Another important issue that remains open is the mechanism controlling the resolution phase in gout. MSU crystal–induced inflammation is generally self-limiting, suggesting that negative feedback loops control the immune response to MSU crystals. Whether such mechanisms involve an inhibition of the maturation of IL-1β or a desensitization to IL-1β responses remains to be investigated. Finally, the study of the physiological function of IL-1β in human gouty inflammation will undoubtedly provide new therapeutic tools to better manage the acute inflammation episodes in patients with gout and provide new insights into the pathology of other autoinflammatory diseases linked to deregulated IL-1β production.

Acknowledgments

We thank Wendy Garrett for discussions and critical reading of the manuscript.

Footnotes

Nonstandard abbreviations used: IL-1R, IL-1 receptor; MSU, monosodium urate; MyD88, myeloid differentiation primary response protein 88; NALP, NACHT, LRR, and pyrin domain–containing protein; NLR, NOD-like receptor; TIR domain, Toll/IL-1R domain; TIRAP, TIR domain–containing adaptor protein; TRAM, TRIF-related adaptor molecule; TRIF, TIR domain–containing adaptor–inducing IFN-β.

Conflict of interest: The authors have declared that no conflict of interest exists.

Citation for this article:J. Clin. Invest.116:2073–2075 (2006). doi:10.1172/JCI29404.

See the related article beginning on page 2262.

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