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1 Surgery, Wayne State University, Detroit, MI, USA; Surgical Service, John D. Dingell VAMC, Detroit, MI, USA
* To whom correspondence should be addressed. E-mail: marc.basson{at}med.va.gov.
We hypothesized that changes in extracellular pressure during inflammation or infection regulate macrophage phagocytosis through modulating the FAK-ERK pathway. Undifferentiated (monocyte-like) or PMA-differentiated (macrophage-like) THP-1 cells were incubated at 37°C with serum-opsonized latex beads under ambient or 20 mmHg increased pressure. Pressure did not affect monocyte phagocytosis, but significantly increased macrophage phagocytosis (29.9±1.8% vs 42.0±1.6%, n=9, p<0.001). THP-1 macrophages constitutively expressed activated FAK, ERK, and Src. Exposure of macrophages to pressure decreased ERK and FAK-Y397 phosphorylation (77.6±7.9%, n=7, p<0.05) but did not alter FAK-Y576 or Src phosphorylation. FAK siRNA reduced FAK expression by over 75% and the basal amount of phosphorylated FAK by 25%, and significantly increased basal macrophage phagocytosis (p<0.05). Pressure inhibited FAK-Y397 phosphorylation in mock-transfected or scrambled-SiRNA-transfected macrophages, but phosphorylated FAK was not significantly further reduced by pressure in cells transfected with FAK SiRNA. Pressure increased phagocytosis in all three groups. However, FAK-SiRNA-transfected cells exhibited only 40% of the pressure effect on phagocytosis observed in scrambled-SiRNA-transfected cells, so that phagocytosis inversely paralleled FAK activation. PD98059 (50 µM), an ERK activation inhibitor, increased basal phagocytosis (26.9±1.8 vs 31.7±1.1%, n=15, p<0.05), but pressure did not further increase phagocytosis in PD98059-treated cells. Pressure also inhibited ERK activation after mock transfection or transfection with scrambled-SiRNA, but transfection of FAK SiRNA abolished ERK inhibition by pressure. Pressure did not increase phagocytosis in MonoMac-1 cells that do not express FAK. Increased extracellular pressure during infection or inflammation enhances macrophage phagocytosis by inhibiting FAK and consequently decreasing ERK activation.
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