Evil humors take their toll as innate immunity makes gouty joints TREM‐ble

Liu‐Bryan, Ru; Terkeltaub, Robert

doi:10.1002/art.21634

Cited by 29 publications

(23 citation statements)

References 33 publications

(44 reference statements)

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“…Limitations of this study include the artificiality of acute injection of free synthetic MSU crystals as a model (2) and the lack of direct assessment of the pathology of inflammation occurring at the serosal surface in the murine MSU crystal-induced peritonitis model. Consequently, we did not evaluate the role of TG2 in the resolution of acute tissue edema or in the process of extracellular matrix remodeling in inflamed tissues.…”

Section: Discussionmentioning

confidence: 99%

Transglutaminase 2 limits murine peritoneal acute gout‐like inflammation by regulating macrophage clearance of apoptotic neutrophils

Rose¹,

Sydlaske²,

Agha-Babakhani³

et al. 2006

Arthritis & Rheumatism

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Objective. Monosodium urate monohydrate (MSU) crystals have remarkable inflammatory potential. However, gouty inflammation is spontaneously self-limited, an occurrence recognized since antiquity. Gouty synovitis is driven and sustained by neutrophil influx. Importantly, macrophage phagocytosis of apoptotic (but not necrotic) neutrophils is antiinflammatory. Therefore, we tested the hypothesis that efficient clearance of apoptotic neutrophils by macrophages is one of the factors that restrains the progression of gouty inflammation. Macrophage expression of transglutaminase 2 (TG2), a multifunctional protein with reciprocally regulated transamidation and purine nucleotidebinding activities, promotes apoptotic leukocyte uptake.In this study, we tested the specific role of macrophage TG2 expression in MSU crystal-induced inflammation. Methods. We studied MSU crystal-induced peritonitis in TG2؊/؊ and congenic TG2 ؉/؉ mice. We also studied the effects of TG2 on apoptotic cell uptake by cultured macrophages.Results. TG2 ؊/؊ mice demonstrated more progressive neutrophilic accumulation than did TG2 ؉/؉ mice, which was associated with delayed clearance of apoptotic neutrophils during MSU crystal-induced peritonitis. We observed defective phagocytosis of apoptotic leukocytes by TG2 ؊/؊ peritoneal macrophages, which was corrected by soluble extracellular TG2. Transamidation catalytic activity of TG2 was not required to mediate macrophage uptake of apoptotic leukocytes. In contrast, the TG2 nucleotide binding site residue K173 was critical for this TG2 function. TG2 bound to GDP, ADP, or ATP (but not to GTP) rescued defective apoptotic leukocyte uptake by TG2 ؊/؊ macrophages. Conclusion. Enhancement of apoptotic neutrophil uptake by macrophage-derived TG2 restrains gout-like neutrophilic peritoneal inflammation. Differential binding of TG2 by purine nucleotides may contribute to clinical variability in the extent and duration of gouty inflammation.In acute gouty arthritis, monosodium urate monohydrate (MSU) crystal deposits in joints trigger inflammation; this process is largely dependent on neutrophil recruitment and proinflammatory mediator generation by resident cells in the joint and by recruited phagocytes (1,2). The capacity of MSU crystals to engage plasma membrane and intracellular innate immune pattern-recognition receptors (Toll-like receptor 2 [TLR-2] and TLR-4, and the NALP3 inflammasome, respectively) modulates crystal inflammatory potential (3-5), as do changes in plasma proteins and complement components that directly interact with MSU crystals (6-8). Despite the remarkable capacity of MSU crystals to induce multiple mediators of inflammation (1,8), self-limitation of the acute gouty attack, typically culminating in spontaneous resolution within 1-2 weeks, has been recognized for more than 2 millenia (8).Natural mechanisms limiting acute gouty inflammation include antiinflammatory disposal of MSU crystals through phagocytosis by mature macrophages, associated with generation of antiinflammatory transforming Dr.

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Section: Discussionmentioning

confidence: 99%

Transglutaminase 2 limits murine peritoneal acute gout‐like inflammation by regulating macrophage clearance of apoptotic neutrophils

Rose¹,

Sydlaske²,

Agha-Babakhani³

et al. 2006

Arthritis & Rheumatism

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“…However, ULT has the paradoxical potential to promote gout flares during the first months of therapy, which is thought to be due to remodeling of MSU crystal deposits in tophi and at the articular cartilage surface, with release of small inflammatory MSU crystals during dissolution of crystal macroaggregates (12).…”

Section: Introductionmentioning

confidence: 99%

Rilonacept (interleukin‐1 trap) for prevention of gout flares during initiation of uric acid–lowering therapy: Results from a phase III randomized, double‐blind, placebo‐controlled, confirmatory efficacy study

Schumacher¹,

Evans²,

Saag³

et al. 2012

Arthritis Care & Research

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Objective. To evaluate the efficacy and safety of the interleukin-1 inhibitor rilonacept (interleukin-1 Trap) for gout flare prevention during initiation of uric acid-lowering therapy (ULT). Methods. In total, 241 adult patients with gout, >2 gout flares within the past year, and a serum urate level >7.5 mg/dl were initiated on allopurinol 300 mg daily and randomly allocated in a 1:1:1 ratio to receive 16 once-weekly subcutaneous injections of placebo, rilonacept 80 mg, or rilonacept 160 mg, with a double (loading) dose on day 1. Allopurinol was titrated to achieve a serum urate level of <6.0 mg/dl. The study was powered for the primary efficacy end point, the number of gout flares per patient through week 16.

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“…In humans, acute gouty arthritis has been suggested to commonly supervene in joints already manifesting lowgrade, subclinical inflammation associated with established tophaceous deposits of MSU crystals (47). In contrast, the mouse air pouch model system does not study a synovial joint and is triggered by injection of relatively large amounts of MSU crystals into a previously noninflamed cavity of animals naive to MSU crystals.…”

Section: Discussionmentioning

confidence: 99%

Engagement of CD14 Mediates the Inflammatory Potential of Monosodium Urate Crystals

Scott

Viriyakosol

et al. 2006

The Journal of Immunology

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108

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Phagocyte ingestion of monosodium urate (MSU) crystals can induce proinflammatory responses and trigger acute gouty inflammation. Alternatively, the uptake of MSU crystals by mature macrophages can be noninflammatory and promote resolution of gouty inflammation. Macrophage activation by extracellular MSU crystals involves apparent recognition and ingestion mediated by TLR2 and TLR4, with subsequent intracellular recognition linked to caspase-1 activation and IL-1β processing driven by the NACHT-LRR-PYD-containing protein-3 inflammasome. In this study, we examined the potential role in gouty inflammation of CD14, a phagocyte-expressed pattern recognition receptor that functionally interacts with both TLR2 and TLR4. MSU crystals, but not latex beads, directly bound recombinant soluble (s) CD14 in vitro. CD14−/− bone marrow-derived macrophages (BMDMs) demonstrated unimpaired phagocytosis of MSU crystals but reduced p38 phosphorylation and ∼90% less IL-1β and CXCL1 release. Attenuated MSU crystal-induced IL-1β release in CD14−/− BMDMs was mediated by decreased pro-IL-1β protein expression and additionally by decreased caspase-1 activation and IL-1β processing consistent with diminished NACHT-LRR-PYD-containing protein-3 inflammasome activation. Coating of MSU crystals with sCD14, but not sTLR2 or sTLR4, restored IL-1β and CXCL1 production in CD14−/− BMDMs in vitro. Gain of function of CD14 directly enhanced TLR4-mediated signaling in response to MSU crystals in transfected Chinese hamster ovary cells in vitro. Last, MSU crystal-induced leukocyte influx at 6 h was reduced by∼75%, and local induction of IL-1β decreased by >80% in CD14−/− mouse s.c. air pouches in vivo. We conclude that engagement of CD14 is a central determinant of the inflammatory potential of MSU crystals.

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Evil humors take their toll as innate immunity makes gouty joints TREM‐ble

Cited by 29 publications

References 33 publications

Transglutaminase 2 limits murine peritoneal acute gout‐like inflammation by regulating macrophage clearance of apoptotic neutrophils

Transglutaminase 2 limits murine peritoneal acute gout‐like inflammation by regulating macrophage clearance of apoptotic neutrophils

Rilonacept (interleukin‐1 trap) for prevention of gout flares during initiation of uric acid–lowering therapy: Results from a phase III randomized, double‐blind, placebo‐controlled, confirmatory efficacy study

Engagement of CD14 Mediates the Inflammatory Potential of Monosodium Urate Crystals

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