Heme oxygenase-1 dysregulation in the brain: implications for HIV-associated neurocognitive disorders

Abstract

Heme oxygenase-1 (HO-1) is a highly inducible and ubiquitous cellular enzyme that subserves cytoprotective responses to toxic insults, including inflammation and oxidative stress. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and multiple sclerosis, HO-1 expression is increased, presumably reflecting an endogenous neuroprotective response against ongoing cellular injury. In contrast, we have found that in human immunodeficiency virus (HIV) infection of the brain, which is also associated with inflammation, oxidative stress and neurodegeneration, HO-1 expression is decreased, likely reflecting a unique role for HO-1 deficiency in neurodegeneration pathways activated by HIV infection. We have also shown that HO-1 expression is significantly suppressed by HIV replication in cultured macrophages which represent the primary cellular reservoir for HIV in the brain. HO-1 deficiency is associated with release of neurotoxic levels of glutamate from both HIV-infected and immune-activated macrophages; this glutamate-mediated neurotoxicity is suppressed by pharmacological induction of HO-1 expression in the macrophages. Thus, HO-1 induction could be a therapeutic strategy for neuroprotection against HIV infection and other neuroinflammatory brain diseases. Here, we review various stimuli and signaling pathways regulating HO-1 expression in macrophages, which could promote neuronal survival through HO-1-modulation of endogenous antioxidant and immune modulatory pathways, thus limiting the oxidative stress that can promote HIV disease progression in the CNS. The use of pharmacological inducers of endogenous HO-1 expression as potential adjunctive neuroprotective therapeutics in HIV infection is also discussed.

Fig. (1)

Model of HIV Neuropathogenesis. HIV infected immune cells, including CD4+ T cells and CD14+ monocytes, circulate through the blood and produce reactive oxygen species (ROS), which can further enhance viral replication and release. Infected or activated immune cells can also release the pro-inflammatory cytokines, TNF-α and IL-1β, which ROS can exacerbate. HIV proteins – gp120, Tat, and Vpr – may also be released and induce toxicity independently of infectious virions. ROS contribute to increased blood brain barrier (BBB) permeability, which can allow for increased entry of infected immune cells (e.g. monocytes) from the blood into central nervous tissue; infected T lymphocytes may also be a source of virus entry into the CNS. As monocytes enter the nervous tissue they differentiate into macrophages, and release IFN-γ in addition to TNF-α. HIV may replicate in macrophages and may be transmitted to microglia, which in turn can further replicate and transmit HIV. Infected or immune-activated microglia or macrophages can produce IFN-γ and TNF-α in a positive feedback loop, and can release a host of neurotoxic factors. Most neurotoxicity is initially limited to synaptic loss and decrease in dendritic density that is dependent on the NMDA-type glutamate receptor. This leads to eventual loss of neuronal function and finally neuronal death. HIV can infect but not productively replicate in astrocytes. Activated astrocytes have abnormal glutamate metabolism, leading to excess glutamate release and excitotoxicity. TNF-α and IL-1β stimulation of astrocytes can further increase glutamate release. Astrocytes, microglia and macrophages are potent inducers of heme oxygenase-1 (HO-1), which is downregulated in infected macrophages and in HIV-infected brains, and thus may also contribute to neuropathogenesis of HIV infection; neurons demonstrate very limited expression of HO-1. Red arrows indicate potential neurotoxins or direct neurotoxic pathways.

Fig. (2)

Signaling Pathways of HO-1. Green arrows represent increased HO-1 expression or activity. Red blocked lines represent inhibition or decreased expression. Several noxious stimuli, highlighted in the green box, are known inducers of HO-1, as well as hemoglobin/heme through the CD163 receptor and LPS through the TLR4 receptor. Anti-inflammatory cytokines are represented in blue; pro-inflammatory cytokines are depicted in red. There are many cytokine signaling loops that involve HO-1 activity or expression, including a positive feedback loop between HO-1 and IL-10 (anti-inflammatory), and a negative feedback loop between HO-1 and TNF-α (pro-inflammatory). Several transcription factors can also bind to the HO-1 promoter (HMOX1 is the gene symbol for HO-1), notably NRF2 at the ARE site, but also AP-1, CREB, and NF-kB can bind to the promoter at independent binding sites and induce HO-1 expression.