Microbial and opsonic effects on macrophage cell cycle progression

Abstract

Macrophages are considered critically important for the mammalian host defense. Their ability to ingest and kill microorganisms is a central aspect of the innate immune defense. Macrophages are also important in the pathogenesis of chronic inflammatory diseases. Hence, the effects of several pathogenic factors, including Fc- or complement-mediated phagocytosis of microbes, opsonic crosslinking of FcR on macrophage cell surface and lethal toxin (LT), an exotoxin secreted by Bacillus anthracis, on macrophage cell cycle progression and their molecular mechanisms were explored in my thesis research. It was discovered that phagocytosis of live or dead Cryptococcus neoformans (Cn), inert polystyrene particles, or activation of Fe receptors (FcR) on cell surface by opsonic crosslinking, can enhance macrophage proliferation. Activation of the ERK signaling pathway was identified to be involved in the cell cycle progression caused by FcR crosslinking during phagocytosis. These results implied that FcR crosslinking on the macrophage cell surface potentially has a novel mitogenic effect. In addition, investigation on effects of anthrax LT on macrophage cell cycle progression discovered that macrophages were arrested in the S phase of cell cycle after the treatment of LT at a sublethal concentration. This phenomenon might be caused by the damage of p53 due to LT toxicity. Investigations are currently carried out to explore this possibility. Macrophage cell cycle status may affect phagocytic efficacy alternatively. FcgammaR and CR3 expression on macrophage-like cells was increased as the cells progressed from G1 to G2 phase. Furthermore, the studies on phagocytosis of live Cn, dead Cn or Cn strains with different virulence revealed interesting differences in phagocytosis efficacy related to macrophage cell cycle status, which indicated that the phagocytosis efficacy in this system as a function of cell cycle is not only related to phagocytic receptor expression but also the macrophage cell cycle status and the nature of ingested particles. In conclusion, these studies in my thesis have further shed lights on the mechanisms by which macrophage cell division plays an important role in the pathogenesis of microbial infection, chronic inflammatory diseases as well as tumorigenesis.