title: Transglutaminase 2 limits murine peritoneal acute gout-like inflammation by regulating macrophage clearance of apoptotic neutrophils.
abstract: 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 nucleotide-binding 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: VA Medical Center, University of California, San Diego, CA 92161, USA. drose@vapop.ucsd.edu
authors.forename: David M
authors.initials: DM
authors.lastname: Rose
authors.forename: Anya D
authors.initials: AD
authors.lastname: Sydlaske
authors.forename: Amir
authors.initials: A
authors.lastname: Agha-Babakhani
authors.forename: Kristen
authors.initials: K
authors.lastname: Johnson
authors.forename: Robert
authors.initials: R
authors.lastname: Terkeltaub
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D006073:Gout / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology*; D010538:Peritonitis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010587:Phagocytosis; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism*; D014527:Uric Acid / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D014527:Uric Acid; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins