Hypoxia Causes an Increase in Phagocytosis by Macrophages in a HIF-1alpha-dependent Manner

Phagocytosis is the process by which microbial pathogens are engulfed by macrophages and neutrophils and represents the first line of defense against bacterial infection. The importance of phagocytosis for bacterial clearance is of particular relevance to systemic inflammatory diseases, which are associated with the development of hypoxia, yet the precise effects of hypoxia on phagocytosis remain largely unexplored. Despite our initial prediction, hypoxia significantly increased the phagocytosis rate of particles in vitro by RAW264.7 and primary peritoneal macrophages and increased phagocytosis of labeled bacteria in vivo by hypoxic mice compared with normoxic controls.
In understanding the mechanisms involved, hypoxia caused no changes in RhoA-GTPase signaling but increased the phosphorylation of p38-MAPK significantly. Inhibition of p38 reversed the effects of hypoxia on phagocytosis, suggesting a role for p38 in the hypoxic regulation of phagocytosis. Hypoxia also significantly increased the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) in macrophages, which was reversed after p38 inhibition, suggesting a link between p38 activation and HIF-1alpha expression.

It is striking that small interfering RNA knockdown of HIF-1alpha reversed the effects of hypoxia on phagocytosis, and overexpression of HIF-1alpha caused a surprising increase in phagocytosis compared with nontransfected controls, demonstrating a specific role for HIF-1alpha in the regulation of phagocytosis. These data indicate that hypoxia enhances phagocytosis in macrophages in a HIF-1alpha-dependent manner and shed light on an important role for HIF-1alpha in host defense.
Systemic hypoxia leads to an increase in phagocytosis by peritoneal macrophages in vivo. (A–C) Mice were exposed to hypoxic or normoxic conditions and the injected i.p. with fluorescently labeled E. coli. Peritoneal macrophages were then harvested, plated on glass cover slips, and examined by confocal microscopy under DIC and FITC optics to evaluate the presence of internalized fluorescent bacteria. (A) Quantification of phagocytosis; *, P   0.05; n _ 3 separate experiments with three mice per experiment involving over 100 macrophages per mouse. Representative images showing a merged DIC and fluorescent image from macrophages, which had been obtained from normoxic (B) and hypoxic (C) mice. Original size bars _ 10 _m. White arrows indicate internalized bacteria.
Anand RJ, Gribar SC, Li J, Kohler JW, Branca MF, Dubowski T, Sodhi CP, Hackam DJ
J Leukoc Biol
2007 Nov
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January 22, 2011
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Last Update
January 22, 2011