Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing

MB Hampton, AJ Kettle… - Blood, The Journal of …, 1998 - ashpublications.org
Blood, The Journal of the American Society of Hematology, 1998ashpublications.org
IN THE 1880s Elie Metchnikoff observed specialized phago-cytic cells ingesting bacteria,
and recognized the importance of phagocytosis as a defense mechanism in multicellular
organisms. 1 Neutrophils are one of the professional phagocytes in humans. They ingest
bacteria into intracellular compartments called phagosomes, where they direct an arsenal of
cytotoxic agents. Metchnikoff noted that ''what substances within the phagocyte harm and
destroy the microbes is quite undecided.''One hundred years on, Mims stated that ''we are …
IN THE 1880s Elie Metchnikoff observed specialized phago-cytic cells ingesting bacteria, and recognized the importance of phagocytosis as a defense mechanism in multicellular organisms. 1 Neutrophils are one of the professional phagocytes in humans. They ingest bacteria into intracellular compartments called phagosomes, where they direct an arsenal of cytotoxic agents. Metchnikoff noted that ‘‘what substances within the phagocyte harm and destroy the microbes is quite undecided.’’One hundred years on, Mims stated that ‘‘we are still profoundly ignorant of the ways in which polymorphs attempt to kill and then to digest the great variety of microorganisms that are ingested.’’2 Our understanding is gradually increasing, but there are still a number of questions to be answered.
It was recognized at an early stage that cytoplasmic granules containing digestive and antibacterial compounds are emptied into the phagosome. 3 Later, it was discovered that phagocytosing neutrophils undergo a burst of oxygen consumption4, 5 that is caused by an NADPH oxidase complex that assembles at the phagosomal membrane. As reviewed by others, 6-8 electrons are transferred from cytoplasmic NADPH to oxygen on the phagosomal side of the membrane, generating first superoxide plus a range of other reactive oxygen species. This oxidative burst is essential for killing of a number of microorganisms, as shown by the susceptibility to infections of individuals with chronic granulomatous disease (CGD), a genetic disease in which the NADPH oxidase is inactive. 9-11 Much is known about the reactive oxygen species released into the extracellular surroundings when neutrophils respond to soluble stimuli. However, the enzymatic and chemical reactions involved in oxidant production are dependent on environmental conditions, which may vary markedly between the phagosome and the extracellular medium. Knowledge of the biochemistry within the phagosome is limited by its inaccessibility to standard detectors and scavengers. Consequently, the oxidant species directly responsible for killing bacteria are still open to speculation. This review focuses on what is known about the chemical composition of the phagosome, the nature and amount of the oxidants generated inside, and on recent information that helps clarify the importance of myeloperoxidase-derived oxidants in killing.
ashpublications.org