Myeloperoxidase: The Good, the Bad, and the Ugly

Neutrophils are one of the first cells to arrive at a site of infection or inflammation. Approximately 2-5% of the dry weight of the neutrophil is made up of myeloperoxidase (MPO). In addition to neutrophils, monocytes are transiently positive for this enzyme. During differentiation into a macrophage (MØ), these cells become negative for MPO. For years the principal function of MPO was viewed as being a participant in the cytotoxic triad. This triad composed of MPO, H2O2, and a halide, usually chloride, is toxic for micro-organisms as well as aberrant mammalian cells. Certainly, MPO in this role is beneficial to the host. Recently, however, the malevolent side of MPO has been exposed. This enzyme is associated with “classical” inflammatory responses such as those found in rheumatoid arthritic joints, Crohn's disease, asthma, and coronary vascular disease. In addition to its participation in inflammatory responses, MPO can function as an antigen and induce the formation of MPO-anti-nuclear cytoplasmic antibody (MPO-ANCA). These antibodies promote acute inflammation and are biological markers for systemic vasculitis, glomerulonephritis, etc. However, the truly ugly aspect of MPO, is its association with the “a-typical” inflammatory responses of neurodegenerative diseases such as, Parkinson's disease (PD), Alzheimer's disease (AD), and multiple sclerosis (MS). Although the above view of MPO may seem quite varied, in reality, it is myopic. Missing from the above, are the unrecognized functions of this enzyme. During the ingestion of cells, particles, and/or cellular debris by neutrophils, MPO is released into the microenvironment where ∼ 40% of the enzyme is inactivated (iMPO). From studies done by the present investigators, it appears that there is a dichotomy of function between MPO and iMPO. MPO functions primarily in situations involving cell killing by the cytotoxic triad and reactive oxygen species (ROS). Conversely, iMPO is more efficient in the induction of cytokines with minimal ROS production and is, therefore, highly immunoregulatory. It is the authors' intention to relate “the good, the bad and the ugly” of an enzyme that plays many known, as well as, unrecognized roles in the immune response.