Abstract
Reactive oxygen species (ROS) produced by brain-infiltrating macrophages and neutrophils, as well as resident microglia, are pivotal to pathogen clearance during viral brain infection. However, unchecked free radical generation is also responsible for damage to and cytotoxicity of critical host tissue bystander to primary infection. These unwanted effects of excessive ROS are combated by local cellular production of antioxidant enzymes, including heme oxygenase-1 (HO-1) and glutathione peroxidase 1 (Gpx1). In this study, we showed that experimental murine herpes encephalitis triggered robust ROS production, as well as an opposing upregulation of the antioxidants HO-1 and Gpx1. This antioxidant response was insufficient to prevent tissue damage, neurotoxicity, and mortality associated with viral brain infection. Previous studies corroborate our data supporting astrocytes as the major antioxidant producer in brain cell cultures exposed to HSV-1 stimulated microglia. We hypothesized that stimulating opposing antioxidative responses in astrocytes, as well as neurons, would mitigate the effects of ROS-mediated neurotoxicity both in vitro and during viral brain infection in vivo. Here, we demonstrate that the addition of sulforaphane, a potent stimulator of antioxidant responses, enhanced HO-1 and Gpx1 expression in astrocytes through the activation of nuclear factor-E2-related factor 2 (Nrf2). Additionally, sulforaphane treatment was found to be effective in reducing neurotoxicity associated with HSV-stimulated microglial ROS production. Finally, intraperitoneal injections of sulforaphane into mice during active HSV infection reduced neuroinflammation via a decrease in brain-infiltrating leukocytes, macrophage- and neutrophil-produced ROS, and MHCII-positive, activated microglia. These data support a key role for astrocyte-produced antioxidants in modulating oxidative stress and neuronal damage in response to viral infection.
Highlights
The first line in defense of the brain against invading viral pathogens is the activation of local microglia and the recruitment of peripheral leukocytes, including macrophages and neutrophils
Direct monitoring of in vivo reactive oxygen species (ROS) to establish the presence of elevated free radicals in the brains of herpes simplex virus (HSV)-1 infected mice has not been performed, but is essential to confirm the role of oxidative stress on herpes encephalitis-associated pathology
Confirming our previous studies, we found that HSV-1 infection resulted in the robust migration of CD45+,CD11bhi macrophages/neutrophils into the brain at 7 d post-infection (p.i.)
Summary
The first line in defense of the brain against invading viral pathogens is the activation of local microglia and the recruitment of peripheral leukocytes, including macrophages and neutrophils. These cells work to eliminate the invading pathogen through the rapid and robust production of reactive oxygen species (ROS). ROS production, while beneficial in clearing invading pathogens, can cause irreparable harm through oxidative damage to crucial host cells. ROS production and its associated oxidative tissue damage contribute to herpes simplex virus (HSV)-1-induced neuropathology [3,4,5]
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