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Translational Nephrology

Uric acid and the immune response*

Michael S. Gersch and Richard J. Johnson

University of Florida, Department of Medicine, Gainesville, Florida, USA

Keywords: caspase; inflammasome; NALP3; uric acid

Classically, the immune system is divided into twobroad categories, consisting of innate and adaptiveimmunity. Adaptive immunity is the specific humoraland cellular response that develops after exposure toa particular antigen. A critical aspect of adaptiveimmunity is the property of memory, with an enhancedresponse on repeat exposure to the same antigen. Onthe other hand, the phyllogenetically ancient innateimmune system is a relatively non-specific first line of defense that does not require prior exposure to theantigen and includes the skin, mucosal barriers, gastricacid and phagocytic cells. Yet how can phagocytic cellsdetermine self and non-self ?

Over the past 10 years, scientists have uncoveredseveral new twists in the innate immune response that

provide phagocytic cells, such as macrophages, withthe capacity to recognize foreign pathogens. These cellsexpress receptors that recognize conserved molecularpatterns on pathogens such as lipopolysaccaride (LPS).The first major family of receptors that detects theseconserved patterns on extracellular pathogens, the toll-like receptors (TLRs), has now been well characterized[1]. Macrophages possess a similar mechanism forresponding to intracellular pathogens such as viruses,termed the inflammasome [2]. The inflammasome isan intracellular multiprotein complex (Figure 1) thatsenses conserved molecular patterns on pathogens andresponds by up-regulating the production of the

endogenous pyrogen, interleukin (IL)-1b [3].This inflammatory response is important for

responding to foreign pathogens, but when the bodygenerates these responses to its own tissues, auto-inflammatory diseases develop. Auto-inflammatory

diseases, such as familial Mediterranean fever (FMF)and Behcet’s disease, are characterized by inappropri-ate inflammatory responses, that in contrast toclassical autoimmune disorders, are not mediated byauto-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 theTLR and inflammasome sensing of these conservedmolecular patterns [1,3,6–8]. Over the past few years,single gene mutations in the inflammasome have beendirectly implicated in several diseases: Muckle–Wellssyndrome, familial cold urticaria, and chronicinfantile neurological cutaneous and articular auto-inflammatory disease [2].

Until recently however, little else was known aboutwhy this complex responds to seemly normal stimuli bycreating inflammation. However, in their recent articlein Nature, Martinon and colleagues [9] expanded ourknowledge on the regulation of this proinflammatory

complex. In both cultured differentiated monocytesas well as isolated mouse peritoneal macrophages, theyshowed that uric acid (UA) crystals as well as calciumpyrophosphate (CPPD) crystals, but not other crystalsof similar shape and size, could activate the inflamma-some to produce mature IL-1b. Furthermore, theyfound that UA and CPPD are more potent activators of the inflammasome than LPS. In order to verify that theIL-1b in their mouse peritoneal macrophage model wasbeing produced by the inflammasome and not fromsome other pathway, they employed inflammasomecomponent (caspase-1, ASC and NALP3) knockoutmice. As predicted, in these knockout mice, peritonealmacrophages stimulated with UA or CPPD did not

produce mature IL-1b, demonstrating that an intactinflammasome is required for this response.

In an acute gouty flare, UA crystals incite atremendous inflammatory response in the synovialspace [10]. The UA crystals directly activate fibroblastsand monocytes present in the articular tissues. Thesecells then elaborate IL-8, a proinflammatory cytokineresponsible for attracting neutrophils to the synovialspace. From Martinon and colleagues’ exciting article,we now know another mechanism by which UA canstimulate inflammation, the inflammasome. If theinflammasome production of IL-1b drives the

*Comment on Martinon F, Petrilli V, Mayor A, Tardivel A,Tschopp J. Gout-associated uric acid crystals activate the NALP3inflammasome. Nature 2006; 440: 237–241.

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@medicine.ufl.edu

Nephrol Dial Transplant (2006) 21: 3046–3047

doi:10.1093/ndt/gfl226

Advance Access publication 24 July 2006

ß The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.For Permissions, please email: journals.permissions@oxfordjournals.org

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initiation of inflammation in gouty flares, then in thefuture, we may be able to treat gouty flares with IL-1bantagonists.

UA has also been identified as having another rolein the innate immune response. Dying cells injectedinto animals along with an antigen creates a strongadjuvant effect and significantly increases the immuneresponse to the initial antigen. Microcrystalline UAreleased from injured cells may be the danger signaltriggering this adjuvant effect through the stimulationof CD8þ T cells [11].

There are now at least three independent mechan-isms by which UA can interact with the immunesystem. UA has also been implicated in the develop-ment of hypertension, cardiovascular disease andthe progression of chronic kidney disease [12–14].Additionally, over the past decade, scientists haverecognized the potential deleterious contributions of the immune response in the development of hyperten-sion, cardiovascular disease and renal disease [15–17].Thus, it is exciting to postulate that UA’s role inthe development of these disease states maybe mediated in part through an immune mechanism.

Conflict of interest statement. Dr Johnson is a consultant for TAPpharmaceuticals.

References

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pathogens. Trends Immunol  2005; 26: 447–4544. Stojanov S, Kastner DL. Familial autoinflammatory diseases:

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Gout-associated uric acid crystals activate the NALP3inflammasome. Nature 2006; 440: 237–241

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the kidney in the induction and maintenance of hypertension.Nephrol Dial Transplant 2006; 21: 260–263

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Tubulointerstitial damage and progression of renal failure.Kidney Int Suppl  2005; S82–S86

Received for publication: 24.3.06Accepted in revised form: 29.3.06

ASC

Caspase-1

Cardinal

NALP3

IL-1βPro--IL-1β

Caspase-1

Uric

acid

Fig. 1. NALP3 inflammasome: 700 kDa five-protein complex con-sisting of NALP3, the adaptor protein ASC, the caspase recruitingprotein cardinal, and a dimmer of caspase-1. The inflammasomeactivates caspase-1 which then converts proIL-1b to active IL-1b.

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