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Myeloperoxidase: a front-line defender against phagocytosed microorganisms
Seymour J Klebanoff1, Anthony J Kettle, Henry Rosen
1Department of Medicine, University of Washington, Seattle, Washington, USA.
Abstract:
Successful immune defense requires integration of multiple effector systems to match the diverse virulence properties that members of the microbial world might express as they initiate and promote infection. Human neutrophils--the first cellular responders to invading microbes--exert most of their antimicrobial activity in phagosomes, specialized membrane-bound intracellular compartments formed by ingestion of microorganisms. The toxins generated de novo by the phagocyte NADPH oxidase and delivered by fusion of neutrophil granules with nascent phagosomes create conditions that kill and degrade ingested microbes. Antimicrobial activity reflects multiple and complex synergies among the phagosomal contents, and optimal action relies on oxidants generated in the presence of MPO. The absence of life-threatening infectious complications in individuals with MPO deficiency is frequently offered as evidence that the MPO oxidant system is ancillary rather than essential for neutrophil-mediated antimicrobial activity. However, that argument fails to consider observations from humans and KO mice that demonstrate that microbial killing by MPO-deficient cells is less efficient than that of normal neutrophils. We present evidence in support of MPO as a major arm of oxidative killing by neutrophils and propose that the essential contribution of MPO to normal innate host defense is manifest only when exposure to pathogens overwhelms the capacity of other host defense mechanisms.
Insights
Myeloperoxidase (MPO) is crucial for effective neutrophil oxidative killing of microbes. Its essential role in innate immunity becomes apparent when host defenses are challenged by pathogens.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Neutrophils are primary responders to microbial invasion, exerting antimicrobial activity within phagosomes.
- Phagosomal antimicrobial action relies on toxins from NADPH oxidase and granule fusion, enhanced by MPO-generated oxidants.
- MPO deficiency is often considered non-essential for neutrophil antimicrobial activity due to a lack of severe infections in patients.
Purpose of the Study:
- To investigate the role of Myeloperoxidase (MPO) in neutrophil-mediated antimicrobial activity.
- To challenge the notion that MPO is merely ancillary to innate host defense.
- To highlight MPO's essential contribution during high pathogen loads.
Main Methods:
- Analysis of microbial killing efficiency in MPO-deficient cells compared to normal neutrophils.
- Review of observations from human MPO deficiency cases and knockout (KO) mouse models.
- Evidence-based support for MPO's function as a primary oxidative killing mechanism.
Main Results:
- Microbial killing by MPO-deficient neutrophils is demonstrably less efficient than by normal neutrophils.
- MPO plays a significant role in the oxidative killing capacity of neutrophils.
- The importance of MPO is most evident when other host defense mechanisms are insufficient.
Conclusions:
- Myeloperoxidase (MPO) is a major component of neutrophil oxidative killing.
- MPO's essential role in innate immunity is revealed under conditions of overwhelming pathogen exposure.
- This study supports MPO as a critical factor in host defense against microbial infections.
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