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.