Continuous recruitment, co-expression of tumour necrosis factor-alpha and matrix metalloproteinases, and apoptosis of macrophages in gout tophi

Gout tophi are characterised by foreign body granulomas consisting of mono- and multinucleated macrophages surrounding deposits of monosodium urate mi crocrystals. After primary formation, granulomas grow associated with degra dation of the extracellular matrix. Based on this background, we have sough t (1) to investigate whether during granuloma's growth new macrophages are recruited into the tophi, (2) to find in situ evidence for macrophages' act ive role in matrix degradation and (3) to examine whether shrunk cells seen within gout tophi are apoptotic. Immunohistochemistry showed that perivasc ular localised mononuclear cells are CD68+, S100A8+, S100A9+, 25F9-, repres enting freshly migrated monocytes/macrophages. In contrast, almost all CD68 + mono- multinucleated cells arranged within granulomas were S100A8-, S100A 9-, 25F9+, representing mature (non-migrating) macrophages. Serial sections revealed that macrophages co-express tumour necrosis factor (TNF)-alpha an d matrix metalloproteinases (MMPs) 2 and 9. In situ end-labelling of fragme nted DNA demonstrated that CD68+ macrophages undergo apoptosis within gout tophi. Our data show that macrophages are continuously recruited into the g out tophi. These macrophages co-produce the proinflammatory cytokine TNF-al pha and two TNF-alpha inducible lytic enzymes, MMP-2 and MMP-9, suggesting that TNF-alpha may induce MMP production followed by matrix degradation wit hin foreign body granulomas. In parallel, macrophages undergo apoptosis, a phenomenon that may restrict the destructive potential of inflammatory macr ophages.