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

Abstract

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.

Inflammatory cells in the formation of tumor-related sarcoid reactions

“…We show that a considerable amount of MRP8-positive and MRP14-positive macrophages occurs in sarcoid reactions within and nearby ECGs. This is similar to sarcoidosis and agrees to the findings of others in granulomas of different etiologies [33][34][35][36]. Because the numbers of MRP8-positive and MRP14-positive macrophages show no significant variation between the different granuloma stages and are similar in sarcoidosis, our data support that freshly migrated macrophages are a constant feature of ECGs and continuously recruited during their formation.…”

“…However, the MRP8 and MRP14 proteins are downregulated in macrophages during their differentiation toward epithelioid cells [34][35][36]. Because epithelioid cells are not selectively recognized by CD68 or any other current marker in routinely processed tissues, our findings concerning a well-working mAb to denatured human ACE [37] are important.…”

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

“…Significantly, tophi are now recognized to continually recruit monocytes that differentiate to macrophages, which is consistent with ongoing remodeling (2). Recently, Yagnik and colleagues elegantly elucidated the capacity of the fully differentiated macrophage to exert antiinflammatory effects on the uptake of MSU crystals (3)(4)(5).…”

Mechanisms of Bone Erosion in Chronic Gout: Lessons Learned from Other Erosive Arthropathies

“…High expression of IL-1β by immune cells has been observed within the tophus [106]; this cytokine may coordinate bone damage in gout through modulation of osteoclastogenesis and the induction of matrix-degrading enzymes by stromal cells [35,107]. Mono-and multi-nucleated macrophages in the tophus core also express TNF-α and MMPs, which can contribute to joint damage via enhanced osteoclastogenesis and tissue degradation respectively [108].…”