NDT Advance Access originally published online on September 8, 2006
Nephrology Dialysis Transplantation 2006 21(11):3046-3047; doi:10.1093/ndt/gfl226
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Uric acid and the immune response*
University of Florida, Department of Medicine, Gainesville, Florida, USA
Correspondence and offprint requests to: Michael S. Gersch, MD, University of Florida, Room CG98, 1600 SW Archer Rd, PO Box 100224, Gainesville, FL 32610-0224. Email: gerscms{at}medicine.ufl.edu
Keywords: caspase; inflammasome; NALP3; uric acid
Classically, the immune system is divided into two broad categories, consisting of innate and adaptive immunity. Adaptive immunity is the specific humoral and cellular response that develops after exposure to a particular antigen. A critical aspect of adaptive immunity is the property of memory, with an enhanced response on repeat exposure to the same antigen. On the other hand, the phyllogenetically ancient innate immune system is a relatively non-specific first line of defense that does not require prior exposure to the antigen and includes the skin, mucosal barriers, gastric acid and phagocytic cells. Yet how can phagocytic cells determine self and non-self ?
Over the past 10 years, scientists have uncovered several new twists in the innate immune response that provide phagocytic cells, such as macrophages, with the capacity to recognize foreign pathogens. These cells express receptors that recognize conserved molecular patterns on pathogens such as lipopolysaccaride (LPS). The first major family of receptors that detects these conserved patterns on extracellular pathogens, the toll-like receptors (TLRs), has now been well characterized [1]. Macrophages possess a similar mechanism for responding to intracellular pathogens such as viruses, termed the inflammasome [2]. The inflammasome is an intracellular multiprotein complex (Figure 1) that senses conserved molecular patterns on pathogens and responds by up-regulating the production of the endogenous pyrogen, interleukin (IL)-1ß [3].
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This inflammatory response is important for responding to foreign pathogens, but when the body generates these responses to its own tissues, auto-inflammatory diseases develop. Auto-inflammatory diseases, such as familial Mediterranean fever (FMF) and Behçet's disease, are characterized by inappropriate inflammatory responses, that in contrast to classical autoimmune disorders, are not mediated by auto-antibodies or antigen-specific T-cells responses [4,5]. It is now clear that several of these auto-inflammatory diseases are caused by mutations in the TLR and inflammasome sensing of these conserved molecular patterns [1,3,6–8]. Over the past few years, single gene mutations in the inflammasome have been directly implicated in several diseases: Muckle–Wells syndrome, familial cold urticaria, and chronic infantile neurological cutaneous and articular auto-inflammatory disease [2].
Until recently however, little else was known about why this complex responds to seemly normal stimuli by creating inflammation. However, in their recent article in Nature, Martinon and colleagues [9] expanded our knowledge on the regulation of this proinflammatory complex. In both cultured differentiated monocytes as well as isolated mouse peritoneal macrophages, they showed that uric acid (UA) crystals as well as calcium pyrophosphate (CPPD) crystals, but not other crystals of similar shape and size, could activate the inflammasome to produce mature IL-1ß. Furthermore, they found that UA and CPPD are more potent activators of the inflammasome than LPS. In order to verify that the IL-1ß in their mouse peritoneal macrophage model was being produced by the inflammasome and not from some other pathway, they employed inflammasome component (caspase-1, ASC and NALP3) knockout mice. As predicted, in these knockout mice, peritoneal macrophages stimulated with UA or CPPD did not produce mature IL-1ß, demonstrating that an intact inflammasome is required for this response.
In an acute gouty flare, UA crystals incite a tremendous inflammatory response in the synovial space [10]. The UA crystals directly activate fibroblasts and monocytes present in the articular tissues. These cells then elaborate IL-8, a proinflammatory cytokine responsible for attracting neutrophils to the synovial space. From Martinon and colleagues’ exciting article, we now know another mechanism by which UA can stimulate inflammation, the inflammasome. If the inflammasome production of IL-1ß drives the initiation of inflammation in gouty flares, then in the future, we may be able to treat gouty flares with IL-1ß antagonists.
UA has also been identified as having another role in the innate immune response. Dying cells injected into animals along with an antigen creates a strong adjuvant effect and significantly increases the immune response to the initial antigen. Microcrystalline UA released from injured cells may be the danger signal triggering this adjuvant effect through the stimulation of CD8+ T cells [11].
There are now at least three independent mechanisms by which UA can interact with the immune system. UA has also been implicated in the development of hypertension, cardiovascular disease and the progression of chronic kidney disease [12–14]. Additionally, over the past decade, scientists have recognized the potential deleterious contributions of the immune response in the development of hypertension, cardiovascular disease and renal disease [15–17]. Thus, it is exciting to postulate that UA's role in the development of these disease states may be mediated in part through an immune mechanism.
Conflict of interest statement. Dr Johnson is a consultant for TAP pharmaceuticals.
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* Comment on Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440: 237–241.
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Accepted in revised form: 29. 3.06
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