Gout tophi are characterised by
foreign body granulomas consisting of mono- and multinucleated macrophages surrounding deposits of
monosodium urate microcrystals. After primary formation,
granulomas grow associated with degradation of the extracellular matrix. Based on this background, we have sought (1) to investigate whether during
granuloma's growth new macrophages are recruited into the tophi, (2) to find in situ evidence for macrophages' active role in matrix degradation and (3) to examine whether shrunk cells seen within
gout tophi are apoptotic. Immunohistochemistry showed that perivascular localised mononuclear cells are CD68+, S100A8+, S100A9+, 25F9-, representing freshly migrated monocytes/macrophages. In contrast, almost all CD68+ mono- and multinucleated cells arranged within
granulomas were S100A8-, S100A9-, 25F9+, representing mature (non-migrating) macrophages. Serial sections revealed that macrophages co-express tumour
necrosis factor (
TNF)-alpha and
matrix metalloproteinases (
MMPs) 2 and 9. In situ end-labelling of fragmented
DNA demonstrated that CD68+ macrophages undergo apoptosis within
gout tophi. Our data show that macrophages are continuously recruited into the
gout tophi. These macrophages co-produce the proinflammatory
cytokine TNF-alpha and two
TNF-alpha inducible lytic
enzymes, MMP-2 and MMP-9, suggesting that
TNF-alpha may induce
MMP production followed by matrix degradation within
foreign body granulomas. In parallel, macrophages undergo apoptosis, a phenomenon that may restrict the destructive potential of inflammatory macrophages.