Metabolic and functional alterations in macrophages induced by essential fatty acid deficiency

Essential fatty acid (EFA) deficiency has been shown to protect against the glomerulonephritis in a murine model of systemic lupus erythematosus. Since macrophages are an important cellular constituent of the inflammatory lesion, the effects of EFA deficiency on the eicosanoid metabolism and function of these cells were determined. EFA-deficient macrophages exhibited a depletion of phospholipid arachidonate and an accumulation of 20:3(n-9); phosphatidylinositol was the phospholipid most affected. When these macrophages were stimulated with unopsonized zymosan, they produced markedly less leukotriene C4 and B4 than control macrophages. EFA-deficient macrophages also synthesized leukotriene C3 from endogenous 20:3(n-9). No leukotriene B3 was detected. In contrast to the effects on leukotriene production, prostaglandin and thromboxane production were only minimally affected by EFA deficiency. When challenged with zymosan, EFA-deficient macrophages released less arachidonate relative to control macrophages and released half again as much 20:3(n-9) as arachidonate. Release of arachidonate from phosphatidylcholine in the EFA-deficient cells was highly selective for arachidonate; however, release of arachidonate from phosphatidylinositol was depressed relative to control and was not selective. Incubation of macrophages with exogenous arachidonate and 20:3(n-9) established that 20:3(n-9) decreased leukotriene C4 and B4 synthesis from arachidonate but did not affect prostaglandin production. To determine the functional effects of the deficiency state, receptor-mediated pinocytosis and phagocytosis were also examined in EFA-deficient cells. EFA-deficient macrophages exhibited a marked reduction in receptor-mediated pinocytosis. Phagocytosis, however, was unaffected by the deficiency state. These effects on macrophage eicosanoid metabolism and function may comprise a significant component of the anti-inflammatory effect of EFA deficiency.