Immunology and Cell Biology (2010) 88, 15–19 & 2010 Australasian Society for Immunology Inc. All rights reserved 0818-9641/10 $32.00 www.nature.com/icb
REVIEW
Innate inflammation and resolution in acute gout William John Martin and Jacquie L Harper Acute gout is an inflammatory arthritis that is controlled by the innate arm of the immune response. Although the causative feature of gout has long been recognized, it is surprising that the cellular activities that underpin the initiation and resolution of acute gout remain poorly described. This review article summarizes what are currently thought to be the key cellular mechanisms at play during an inflammatory episode of acute gout. The emerging role of mononuclear phagocytes is highlighted as having a central role in both the initiation and resolution of acute gout, and the interplay between monocytes and other elements of the innate immune response, including neutrophils, and complement protein activation are discussed. Immunology and Cell Biology (2010) 88, 15–19; doi:10.1038/icb.2009.89; published online 24 November 2009 Keywords: gout; inflammation; innate immunity; MSU crystals
Gout is an intensely painful form of arthritis with a documented history spanning several thousands of years.1,2 An attack of gout is characterized by abrupt onset of joint inflammation, that, in the absence of clinical intervention, will spontaneously resolve over 7–10 days.3 One clear distinction between gout and other arthritides is that the causative agent in gout is known. An attack of gout is triggered by the deposition of monosodium urate (MSU) crystals in the joint and MSU crystal-induced inflammation is widely recognized as being initiated and driven by components of the innate immune system. Stimulation of the cellular inflammatory cascade is commonly associated with activation of mononuclear phagocytes leading to the generation of a host of proinflammatory mediators, including interleukin (IL)-1b, tumor necrosis factor (TNF)a, IL-6, IL-8 and other activators of CXCR-2, as well as a characteristic recruitment of inflammatory monocytes and neutrophils into the joint synovium.4–9 The specific mechanisms by which the innate immune system recognizes or ‘senses’ MSU crystals are not clearly defined. However, a resurgence of interest in MSU crystal inflammation has led to the identification of MSU crystals as a potential ‘danger signal’ through activation of macrophages via the innate Nod-like receptors, more specifically the NALP-3 inflammasome.10 This work serves to highlight a key role for phagocytic mononuclear cells in initiation of proinflammatory responses to MSU crystals. Limited research has been undertaken into the processes involved in switching off MSU crystal-induced inflammation. Potential shutdown mechanisms have been suggested, and these mechanisms appear to rely heavily on the differentiation state of mononuclear phagocytes, including their phagocytic capacity, in the joint. This review aims at providing a current snapshot of how various cellular and non-cellular components of the innate immune system
can contribute to the profile of MSU crystal-induced inflammation and resolution. MECHANISMS OF INFLAMMATION Mononuclear phagocytes in the initiation of acute gouty inflammation Mononuclear phagocytes are thought to have a central role in gout, in which they contribute to all stages of inflammation from recognition of MSU crystals through to resolution. In vitro studies have shown that monocyte cell lines produce classical proinflammatory cytokines, most importantly IL-1b, after exposure to MSU crystals.11,12 In contrast, cell lines expressing a more differentiated, macrophagelike phenotype predominantly produced transforming growth factor (TGF)b,13 a cytokine commonly linked with resolution of inflammation and tissue repair. As a result, it has been hypothesized that MSU crystal-recruited monocytes, rather than macrophages, drive gouty inflammation, whereas subsequent monocyte differentiation into macrophages has a role in resolution. However, other studies indicate that this may not represent the whole picture. The depletion of resident macrophages has been shown to result in the abrogation of MSU crystal-induced IL-1b production and neutrophil recruitment in vivo.14 Several other papers also show that MSU crystals elicit a classical proinflammatory response (IL-1b, TNFa, MCP-1, IL-18, iNOS and upregulation of TREM-1) from primary and bone marrow-derived macrophages,10,15–19 further emphasizing a key role for macrophages in the initiation of the inflammatory cascade. Monocytes have been implicated in driving gouty inflammation in studies using in vitro experimental systems; yet, surprisingly few studies have looked at the function and phenotype of MSU crystalrecruited monocytes in vivo. It has been reported that early MSU
Arthritis and Inflammation Group, Malaghan Institute of Medical Research, Wellington, New Zealand Correspondence: Dr JL Harper, Malaghan Institute of Medical Research, PO Box 7060, Wellington 6242, New Zealand. E-mail:
[email protected] Received 5 October 2009; revised 20 October 2009; accepted 23 October 2009; published online 24 November 2009
Innate inflammation and resolution WJ Martin and JL Harper 16
crystal-recruited monocytes do not respond to MSU crystals, indicating that they may not be responsible for the amplification of inflammation in vivo.14 However, further studies are needed to determine whether these recruited monocytes alter their responses during the latter stages of inflammation and have an active role in gouty inflammation by promoting either inflammation or resolution, or whether they are principally recruited to replenish the local resident macrophage population. Recognition of monosodium urate crystals An intriguing aspect of inflammation in gout is that it arises from the recognition of MSU in crystalline form. Although it is unlikely that innate cells express dedicated receptors for detecting MSU crystals, pattern recognition receptors have been implicated as contributing to the inflammatory response. In both TLR-2 and TLR-4 knockout mice, IL-1b production and neutrophil infiltration are decreased in a murine air pouch model of MSU crystal-induced inflammation.20 It is unlikely that TLRs have the capacity to detect MSU crystals directly, and in this instance it appears that binding of soluble CD14 to MSU crystals may mediate MSU crystal-dependent engagement of TLRs in this model.21 In another study, various TLRs, including TLR-2 and TLR-4, have been shown to be dispensable in a peritoneal model of acute gout,17 therefore raising the question of whether specific TLR signalling is essential for the induction of MSU crystal-induced inflammation. In fact, rather than having a role in recognition of MSU crystals, there are data indicating that TLRs may contribute to MSU crystal-induced inflammation indirectly by regulating synthesis of pro-IL-1b.17,21 There is now a growing body of evidence showing that the primary mechanism involved in initiating a gout attack is associated with the phagocytosis of MSU crystals. Internalized MSU crystals destabilize phagosomes leading to phagosome rupture and activation of the NALP-3 inflammasome, a cytosolic enzyme complex that is responsible for the processing of pro-IL-1b.22 This activation pathway is not specific to MSU crystals, as other crystals and particulates have been shown to trigger the inflammatory cascade leading to NALP-3 activation.22 However, it is possible that subtle differences in the physical properties of different inflammatory crystals, including surface charge and size, result in a variation in the intensity of the inflammatory response, as illustrated by the less severe inflammation triggered by calcium pyrophosphate dihydrate in pseudo gout.23–26 Complement To date the number of studies undertaken to analyze the role of complement in gout inflammation have been limited. Nevertheless, there is strong evidence that complement has an instrumental role in the inflammatory response to MSU crystals. As a starting point, active complement is greatly increased in synovial fluid from patients with acute gout.27–29 The functional importance of complement has also been illustrated in animal models of acute gout in which depletion of, or deficiency in, complement components results in abrogation of MSU crystal-induced inflammation.30–32 Experiments with human serum in vitro have shown that MSU crystals have the capacity to activate a broad range of complement proteins of both the classical and alternative complement pathways, including C1,33 C2, C4, C5,34 C3,29 and factor B.35 Activation of the classical complement pathway is generally associated with binding of IgM or IgG to the C1q molecule. However, although IgG can be found coating MSU crystals, the activation of C1q and the classical pathway does not require the presence of IgG in MSU activation.33 In fact, the activation of many of the complement proteins appears to involve Immunology and Cell Biology
direct interactions with the negatively charged crystal surface, including assembly of a functional C5 convertase complex at the crystal surface resulting in the generation of active C5a and C5b in serum.36 It has not yet been shown which aspects of complement have direct relevance to gout; however, C5-dependent neutrophil chemotactic ability has been shown in MSU-treated human serum in vitro,36 indicating a potential role for complement in amplifying neutrophil recruitment. Another potential role for complement in neutrophil recruitment has been identified using rabbits that cannot assemble the membrane attack complex because of a C6 deficiency. These rabbits showed a marked reduction in the intraarticular levels of the neutrophil chemoattractant IL-8, as well as decreased neutrophil infiltration during experimental gout.32 It therefore appears that the membrane attack complex has a role to play in both cytokine production and neutrophil recruitment in gouty inflammation. Synoviocytes exposed to complement complexes isolated from rheumatoid arthritic joints have been shown to produce both IL-8 and the monocyte chemoattractant MCP-1,37 and MSU crystalinduced MCP-1 production by synoviocytes has been reported in a rabbit model of knee synovitis.38 Indirectly, these data indicate that complement may also facilitate monocyte migration in gout by inducing chemokine production by cells in the synovial membrane. Inflammatory cell recruitment and activation The recruitment of neutrophils into the synovial space is a characteristic feature of an acute gout attack.39 This recruitment appears to rely heavily on MyD88-dependent IL-1b receptor (IL-1R) signalling in non-hemopoietic cells.17 Clinical studies testing the therapeutic efficacy of the IL-1R antagonist anakinra also identify IL-1R as a promising therapeutic target in gout.40 The specific non-hemopoietic cells expressing IL-1R have not been identified; however, endothelial cells are potential candidates. These cells have been shown to aid cellular extravasation through IL-1bdependent activation of the adhesion molecule E-selectin, a process that is crucial for neutrophil recruitment in vivo.41 Analysis of aspirates collected from the joints of patients during acute gouty episodes shows that the synovial fluid contains neutrophils that have phagocytosed MSU crystals.42 MSU crystal stimulation of neutrophils leads to the production of large quantities of the chemokine IL-8, an important mediator for the recruitment of neutrophils in gout.7,8 Neutrophils stimulated with MSU crystals also show a significant delay in apoptosis, presumably leading to persistent and prolonged activity during active gouty inflammation.43 Both increased recruitment and prolonged lifespan likely work together to accumulate large numbers of neutrophils within the joint. Monosodium urate crystal-recruited neutrophils actively produce superoxide in vivo and MSU crystal stimulation also triggers the generation of neutrophil superoxide in vitro.44 The generation of MSU-induced superoxide is amplified in the presence of inflammatory mediators such as TNFa and granulocyte-macrophage colonystimulating factor. This indicates that the inflammatory capacity of neutrophils may be significantly higher in the joint in which several pro-inflammatory molecules are present to moderate neutrophil functions during an attack.45 It has not been established whether neutrophils directly cause tissue and joint damage in gout, but in other models of inflammatory arthritis, inhibition of superoxide through elevation of endogenous levels of superoxide dismutase results in diminished joint swelling, cellular infiltration and tissue damage.44,46,47 In addition to neutrophil infiltration, monocytes are recruited in response to MSU crystals. Although monocyte trafficking and
Innate inflammation and resolution WJ Martin and JL Harper 17
function has been studied less extensively in gout compared with neutrophils, synoviocytes have been identified as a key source of MCP1 production in a neutrophil-depleted model of MSU crystal-induced inflammation.38 Interestingly, this study also showed that only 50% of MCP-1 production was dependent on IL1b and TNFa, and that MCP1 production accounts for approximately half of the MSU crystalinduced monocyte recruitment, indicating that multiple pathways control monocyte infiltration. MECHANISMS OF RESOLUTION A clear area of interest in gout research has been to unravel the mysteries behind the self-limiting nature of a gout attack. Understanding the mechanisms that lead to gout resolution has the potential to provide insights into new therapies aimed at triggering inflammatory resolution and abrogating clinical disease progression. This area of research has not yet provided a conclusive model on how gout resolution occurs, but a range of potential shutdown mechanisms have been suggested based on the few experimental findings available. Crystal binding of inhibitory proteins Monosodium urate crystals bind a myriad of different proteins from immunoglobulins to complement. The crystal surface itself is a site of dynamic protein exchange in which the makeup of the surface proteins can reflect the progression of the inflammatory response. Analysis of proteins on MSU crystals isolated from both gout patients and animal models during the early stages of inflammation shows that crystals are initially coated with complement-activating IgG. During the resolution phase, IgG is displaced by apolipoproteins, predominantly apoliprotein B and apoliprotein E.48 Apoliprotein B and apoliprotein E-coated MSU crystals fail to elicit the same respiratory burst that is observed with uncoated crystals.49,50 It is not yet clear whether apolipoproteins actively shut down inflammation or simply mask the crystal surface to prevent recognition by cells. In the case of the latter, binding of apolipoproteins to MSU crystals may serve as a mechanism to avoid perpetual activation of infiltrating and resident inflammatory cells, thereby averting an ongoing and sustained inflammatory response. This method of masking MSU crystal recognition may also explain why MSU crystals can be found in the synovial aspirates of gout sufferers in the absence of active inflammation.51 Transforming growth factor-b1 Transforming growth factor-b1 is currently thought to be the prime mediator in the active resolution of gouty inflammation. Elevated levels of TGF-b1 have been reported in the synovial fluid of gout patients, suggesting that TGF-b1 may be involved in inflammatory quiescence during intercritical periods.52,53 A role for TGF-b1 in gouty inflammation has been further strengthened by a recent study of a group of Taiwanese men showing that gout patients carrying the TT genotype for the TGF-b1 polymorphism 869T/C have a greater number of tophi and thus show a more advanced disease state.54 The ability of TGF-b1 to switch off MSU-induced inflammation has been shown in a rat air pouch model of gout in which the introduction of extraneous TGF-b1 significantly attenuated cellular recruitment.55 In vitro studies have shown that TGF-b1 decreases IL-1b production and IL-1 receptor expression,56,57 both of which play an important role in the initiation of gout inflammation and subsequent inflammatory cell recruitment.58 Therefore, it is highly likely that TGF-b1 has a role in shutting down gouty inflammation through this mechanism. Despite the indications of TGF-b1 involvement in gout, there is still a lack of information on the potential mechanisms and cellular sources of endogenous TGF-b1 in gout. Mononuclear phagocytes
have been identified as the most likely cellular candidates for generating TGF-b1 in response to MSU crystals. Macrophages that have been matured in vitro from blood monocytes of healthy individuals actively produce TGF-b1 on stimulation with MSU crystals.13 In addition, resolving skin blisters induced using the irritant cantharidin contain a population of leukocytes that produce TGF-b1 on ex vivo exposure to MSU crystals.13 This has led to the hypothesis that MSU-crystalrecruited monocytes differentiate toward a macrophage phenotype that can produce TGF-b1 in response to MSU crystal exposure within the joint space. Apoptosis and cell clearance Another likely mechanism for triggering resolution in gout is the clearance of apoptotic leukocytes by macrophages. In acute inflammation, the recognition and subsequent phagocytosis of apoptotic neutrophils by macrophages results in the production of TGFb,59 illustrating a switch in the macrophage from an activated inflammatory phenotype to one that promotes resolution. Neutrophil phagocytosis also provides the signal for migration of inflammatory macrophages from sites of inflammation into the lymphatic system,60 thereby removing key cells involved in the initiation and propagation of the inflammatory cascade. Although it has yet to be confirmed clinically, it has been suggested that impaired clearance of neutrophils by macrophages may contribute to the severity and duration of a gout attack.61 Whether neutrophil clearance is orchestrated predominantly by the original resident macrophage population or by newly differentiated macrophages is yet to be determined. OVERVIEW OF THE DISEASE PROCESS On the basis of the research findings to date, the acute, self-resolving inflammatory profile of MSU crystal-induced inflammation in gout is dependent on a variety of different components of the innate immune system working in concert (Figure 1). During the inflammatory phase, MSU crystals are phagocytosed by resident macrophages inducing the production of inflammatory cytokines and chemokines, including IL-1b, IL-8 and TNFa. The local proinflammatory response and neutrophil recruitment are then amplified after binding of IL-1b to the IL-1R on endothelial cells, triggering additional production of neutrophil chemoattractants and neutrophil infiltration facilitated by production of E-selectins. At the site of inflammation, neutrophils may be activated by MSU crystals and further perpetuate neutrophil recruitment through the production of IL-8. Cleavage of complement proteins also serves to initiate and augment chemokine production and neutrophil recruitment. Monocyte recruitment in response to MSU crystals is partially driven by MCP-1 production by synoviocytes, which is also augmented, in part, through IL-1R signalling. Once recruited, monocytes begin a process of differentiation that appears to correlate with the resolution phase of the inflammatory response. As recruited monocytes develop a macrophage phenotype, they can phagocytose apoptosing neutrophils and produce TGFb, blocking IL-1b production and initiation of the inflammatory cascade, thereby facilitating inflammatory cell clearance and resolution. At the same time, MSU crystal recognition is masked by the accumulation of inhibitory proteins on the crystal surface rendering them inactive and cannot initiate a secondary inflammatory response in newly differentiated macrophages. Differentiation of the recruited monocytes may also provide a mechanism for repopulation of the resident macrophage population. The recent re-ignition of interest in MSU crystal-induced inflammation has led to significant advances in our understanding of the Immunology and Cell Biology
Innate inflammation and resolution WJ Martin and JL Harper 18 Neutrophils
E-selectin Monocytes MCP-1
Resolution
Inflammation
Endothelium
C5a C5b-9 C3a IgG
IL-1β IL-8 TNFα IL-6
Inflammatory MSU
IL-8
– O2 O– 2 IL-1β O– 2
Resident macrophages
ApoB ApoE
Synovium
Differentiation
Apoptosis TGFβ
Non-inflammatory MSU Crystal-protein interactions
Newly differentiated macrophages
Resident macrophages
Crystal-leukocyte interactions
Figure 1 Proposed model of monosodium urate (MSU) crystal-induced inflammation. Complement proteins are cleaved and activated at the crystal surface, whereas tissue-associated macrophages phagocytose MSU crystals and generate proinflammatory cytokines. These signals initiate and augment neutrophil recruitment, aided by the activation of adhesion molecules such as E-selectin on endothelial cells. Recruited neutrophils are activated after contact with MSU crystals and generate superoxide and interleukin (IL)-8, augmenting neutrophil accumulation. Monocytes may be recruited in a macrophageindependent manner, through endothelial generation of IL-1b-dependent MCP-1. Differentiation of recruited monocytes into macrophages allows transforming growth factor (TGF)b production after either MSU stimulation or uptake of apoptotic neutrophils and contributes to resolution. Simultaneously, coating of MSU crystals with apoliprotein (Apo) B and Apo E blocks ongoing activation of complement proteins and local cells. After resolution, newly differentiated macrophages replenish the resident macrophage population and reset the environment in the joint for a future challenge. Dashed arrows represent cell recruitment.
inflammatory mechanisms involved in gout; however, there are many important questions that remain to be addressed. The exact method by which the innate immune system recognizes crystals remains elusive and the hypothesized mechanisms of resolution, although likely, are yet to be illustrated conclusively in vivo. Although neutrophils are widely recognized as a clinical feature of gout, mononuclear phagocytes are beginning to assume center stage as key orchestrators of the inflammatory response. As such, the specific contribution(s) of recruited monocytes at different stages of the inflammatory response in vivo need to be clarified to determine whether they are driving or resolving inflammation, or both. Answers to these and many other questions will no doubt provide important insights into new potential therapeutic options for improved gout therapy, but will also serve to enhance our understanding and appreciation of the multi-level interactions between the innate and adaptive immune systems.
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