Rotenone exposure has emerged as an environmental risk factor for inflammation-associated
neurodegenerative diseases. However, the underlying mechanisms responsible for the
harmful effects of rotenone in the brain remain poorly understood. Herein, we report
that myeloperoxidase (MPO) may have a potential regulatory role in rotenone-exposed
brain-resident immune cells. We show that microglia, unlike neurons, do not undergo
death; instead, they exhibit distinctive activated properties under rotenone-exposed
conditions. Once activated by rotenone, microglia show increased production of reactive
oxygen species, particularly HOCl. Notably, MPO, an HOCl-producing enzyme that is
undetectable under normal conditions, is significantly increased after exposure to
rotenone. MPO-exposed glial cells also display characteristics of activated cells,
producing proinflammatory cytokines and increasing their phagocytic activity. Interestingly,
our studies with MPO inhibitors and MPO-knockout mice reveal that MPO deficiency potentiates,
rather than inhibits, the rotenone-induced activated state of glia and promotes glial
cell death. Furthermore, rotenone-triggered neuronal injury was more apparent in co-cultures
with glial cells from Mpo(-/-) mice than in those from wild-type mice. Collectively,
our data provide evidence that MPO has dual functionality under rotenone-exposed conditions,
playing a critical regulatory role in modulating pathological and protective events
in the brain.
Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier
Inc. All rights reserved.