Immunology and Cell Biology (2010) 88, 13–14 & 2010 Australasian Society for Immunology Inc. All rights reserved 0818-9641/10 $32.00 www.nature.com/icb
EDITORIAL
Out with gout: opening the door on acute inflammation Immunology and Cell Biology (2010) 88, 13–14; doi:10.1038/icb.2009.99
G
out is a form of autoinflammatory arthritis driven by the innate immune response to the deposition of monosodium urate (MSU) crystals in the joint and periarticular tissues. Once considered to be the ‘disease of kings’, the prevalence of gout is increasing worldwide, establishing gout as a common disease in the western world.1–3 Historically, gout research has played the reluctant bridesmaid to other arthritides; however, recent developments in the field have placed MSU crystal-induced inflammation back on the radar and have opened up a new understanding of the physiological relevance of MSU crystal-induced inflammation. A number of studies have now identified MSU crystals as a native adjuvant that is capable of enhancing antigen-specific immune responses.4 In this Special Feature of ICB, several key aspects of gouty arthritis are reviewed. In their Special Feature review, Liu-Bryan and colleagues discuss how the MSU crystal-induced inflammatory pathway begins with the activation of the NALP3 inflammasome5 in monocyte/macrophages, leading to engagement of the innate arm of the immune system. Low-level, local MSU crystal-induced inflammation may be advantageous in boosting adaptive immunity when tightly regulated. However, excessive, physiologically irrelevant, MSU crystal deposition results in an attack of acute gout. Innate cells of the monocyte/ macrophage lineage are implicated as having a key role in initiating and driving inflammation in gout, but have also been implicated in resolving a gout attack.6,7 In their contribution to the Special Feature, Martin and Harper put forward a working model of the progression of an acute gout attack in vivo that focuses on the contribution of resident macrophages and infiltrating monocytes, and outlines cellular and molecular interactions at the site of inflammation that dictate pro-inflammatory versus anti-inflammatory function. A characteristic feature of gout inflammation is the infiltration of large numbers of neutrophils. This has made neutrophil inflammatory responses to MSU crystals a significant focus of gout research to date. In their Special Feature review, Popa-Nita and colleagues present the current understanding of the early events involved in the activation of human neutrophils, providing insight into the nature of the strong inflammatory response of neutrophils to MSU crystals. Neutrophil activation triggers the production of a number of immune mediators that are generally associated with proinflammatory functions and/or killing. One such family of proteins are the calgranulins, S100A8, S100A9 and S100A12. These proteins are also produced by monocytes and macrophages and are found to be elevated in the synovial fluid of acute and chronic gout patients.8 However, the presence of calgranulins within inflamed joints may not necessarily indicate inflammation. In their Special Feature review, Perera et al. discuss the involvement of calgranulins in inflammation and present
emerging evidence to support a potential regulatory role for S100 proteins in inflammatory arthritides, including gout. To date, the majority of gout research has concentrated around macrophage, monocyte and neutrophil responses to MSU crystals. As such the involvement of other cell types has been largely ignored. It appears that this is about to change. Although activation of innate immunity by MSU has been shown to enhance adaptive immune responses, it has now been shown that T cells may play a part in shutting down the NALP3 inflammasome, thereby providing a feedback loop to ameliorate innate inflammation.9 Another cell present in gouty joints is the natural killer (NK) cell. These cells have been reported to influence adaptive immune responses through their interactions with dendritic cells and T cells.10 Following along from this, Empson and co-workers, in their contribution to the Special Feature, discuss the potential for NK cells to undertake a similar modulatory role in gouty inflammation. Gout research is emerging out of the shadows and is delivering new insights into the intricacies of acute inflammation. The collective reviews in this issue highlight some of the recent advances in the field and illustrate the broad application of previous and future findings to the wider field of immunology and our understanding of gouty inflammation. The challenge is to think outside the square. Can inflammatory cells and mediators orchestrate their own end? Are innate and adaptive immunity co-dependent for effective immune regulation? Can we use adaptive immune therapy to treat innate inflammation? Answers to these and many as yet unidentified questions could be just around the corner. Jacquie L Harper Malaghan Institute of Medical Research, Wellington, New Zealand E-mail:
[email protected]
1 Klemp P, Stansfield SA, Castle B, Robertson MC. Gout is on the increase in New Zealand. Ann Rheum Dis 1997; 56: 22–26. 2 Mikuls TR, Farrar JT, Bilker WB, Fernandes S, Schumacher Jr HR, Saag KG. Gout epidemiology: results from the UK General Practice Research Database, 1990–1999. Ann Rheum Dis 2005; 64: 267–272. 3 Kim KY, Ralph Schumacher H, Hunsche E, Wertheimer AI, Kong SX. A literature review of the epidemiology and treatment of acute gout. Clin Ther 2003; 25: 1593–1617. 4 Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 2003; 425: 516–521. 5 Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440: 237–241. 6 Yagnik DR, Evans BJ, Florey O, Mason JC, Landis RC, Haskard DO. Macrophage release of transforming growth factor beta1 during resolution of monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum 2004; 50: 2273–2280.
Editorial 14 7 Martin WJ, Walton M, Harper J. Resident macrophages initiating and driving inflammation in a monosodium urate monohydrate crystal-induced murine peritoneal model of acute gout. Arthritis Rheum 2009; 60: 281–289. 8 Rouleau P, Vandal K, Ryckman C, Poubelle PE, Boivin A, Talbot M et al. The calciumbinding protein S100A12 induces neutrophil adhesion, migration, and release from bone marrow in mouse at concentrations similar to those found in human inflammatory arthritis. Clin Immunol 2003; 107: 46–54.
Immunology and Cell Biology
9 Guarda G, Dostert C, Staehli F, Cabalzar K, Castillo R, Tardivel A et al. T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes. Nature 2009; 460: 269–273. 10 Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G. Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med 2002; 195: 327–333.
