Noninflammatory phagocytosis of monosodium urate monohydrate crystals by mouse macrophages - Implications for the control of joint inflammation in gout

Objective. We have hypothesized that the process of monocyte to macrophage differentiation may alter the inflammatory response of mononuclear phagocyt es to the uptake of monosodium urate monohydrate (MSU) crystals. Methods. Eight mouse monocyte/macrophage cell lines were arranged in increa sing order of differentiation, as judged by expression of the macrophage ma rkers F4/80 and BM 8 and by phagocytic capacity. Secretion of tumor necrosi s factor alpha (TNF alpha) in response to MSU was measured by enzyme-linked immunosorbent assay. Results. The panel of monocyte/macrophage cell lines revealed a close linka ge between the state of differentiation and the capacity of the cells to in gest MSU crystals. TNF alpha production, however, was not linked to phagocy tic ability. Peak TNF alpha levels were synthesized by cells at an intermed iate state of differentiation (3.2-14.1 ng/ml), whereas mature macrophages, which efficiently phagocytosed crystals, did not secrete TNF alpha. Mature cell lines produced TNF alpha when stimulated with zymosan (5.9-6.2 ng/ml) , but this was abolished by coincubation with MSU crystals. Suppression of the zymosan response was not due to apoptosis or steric hindrance by MSU cr ystals. Culture supernatants from mature macrophages did not stimulate endo thelial cell activation, in contrast to MSU-treated cells at an earlier sta ge of differentiation, which stimulated intercellular adhesion molecule 1 e xpression on sEND endothelioma cells through the release of TNF alpha (inhi bited 80.6% by anti-TNF alpha). Conclusion. We demonstrated that phagocytosis and TNF alpha production are distinct events in the response of mononuclear phagocytes to urate crystals , and these events can be distinguished at the level of macrophage differen tiation. The noninflammatory removal of urate crystals by mature macrophage s defines a new pathway that may be important in controlling the developmen t of acute gout in patients with hyperuricemia.